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Julio Aliberti, MS, PhD
is focused on defining the mechanisms underlying the induction and regulation of immune responses to intracellular pathogens, including Toxoplasma gondii and Mycobacterium tuberculosis, microbes that cause an immense burden of morbidity and mortality in the world at large. The ultimate goal of this research program is the development of novel preventive and therapeutic approaches to these pathogens.
Assistant Professor, UC Department of Pediatrics
BSc: Biology, FFCL Barao de Maua, Ribeirao Preto, Brazil, 1994.
MS: Immunology, FMRP / USP, Ribeirao Preto, Brazil, 1996.
PhD: Immunology, FMRP / USP, Ribeirao Preto, Brazil, 1998.
Zoller EE, Lykens JE, Terrell CE, Aliberti J, Filipovich AH, Henson PM, Jordan MB. Hemophagocytosis causes a consumptive anemia of inflammation. J Exp Med. 2011 Jun 6;208(6):1203-14.
Lykens JE, Terrell CE, Zoller EE, Divanovic S, Trompette A, Karp CL, Aliberti J, Flick MJ, Jordan MB. Mice with a selective impairment of IFN-gamma signaling in macrophage lineage cells demonstrate the critical role of IFN-gamma-activated macrophages for the control of protozoan parasitic infections in vivo. J Immunol. 2010 Jan 15;184(2):877-85.
Machado FS, Aliberti J. Lipoxins as an immune-escape mechanism. Adv Exp Med Biol. 2009;666:78-87.
Machado FS, Aliberti J. Role of lipoxin in the modulation of immune response during infection. Int Immunopharmacol. 2008 Oct;8(10):1316-9. Machado FS, Esper L, Dias A, Madan R, Gu Y, Hildeman D, Serhan CN, Karp CL, Aliberti J. Native and aspirin-triggered lipoxins control innate immunity by inducing proteasomal degradation of TRAF6. J Exp Med. 2008 May 12;205(5):1077-86.
Yamauchi LM, Aliberti J, Baruffi MD, Portela RW, Rossi MA, Gazzinelli RT, Mineo JR, Silva JS. The binding of CCL2 to the surface of Trypanosoma cruzi induces chemo-attraction and morphogenesis. Microbes Infect. 2007;9:111-8.
Liu CH, Machado FS, Guo R, Nichols KE, Burks AW, Aliberti J, Zhong XP. Diacylglycerol kinase zeta regulates microbial recognition and host resistance to Toxoplasma gondii. J Exp Med. 2007;204:781-92.
Liu CH, Fan YT, Dias A, Esper L, Corn RA, Bafica A, Machado FS, Aliberti J. Cutting Edge: Dendritic cells are essential for in vivo interleukin-12 production and development of resistance against Toxoplasma gondii infection in mice. J. Immunol. 2006;177:31-5.
Arita M, Bianchini F, Aliberti J, Sher A, Chiang N, Hong S, Yang R, Petasis NA, Serhan C. Stereochemical assignment, anti-inflammatory properties, and receptor for the omega-3 lipid mediator resolving E1. J. Exp. Med. 2005;201:713-22.
Bafica A, Scanga C, Serhan C, Machado F, White S, Sher A, Aliberti J. Host control of Mycobacterium tuberculosis is regulated by 5-lipoxygenase-dependent lipoxin production. J. Clin. Invest. 2005;115:1601-6.
Long-term Immunity Against Toxoplasmosis. Principal Investigator. National Institute of Allergy and Infectious Diseases. April 2008 – March 2013. #R01 AI033325.
Control of immune responses by lipoxins during tuberculosis. Principal Investigator. National Institutes of Health. April 2008 – March 2013. #01AI075038.
Artem Barski, PhD
Epigenetics; epigenomics; immunology; T cell memory
Visit the Barski Lab
Artem Barski, PhD, is interested in epigenetic and transcriptional regulation of gene expression. During his post-doctoral training in Keji Zhao lab at NIH, Dr. Barski took part in the development of ChIP-Seq, a revolutionary method that combines ChIP with the next-generation sequencing. ChIP-Seq allows genome-wide mapping of chromatin modifications and transcription factor binding sites with resolution and sensitivity far exceeding older methods. Together with his NIH colleagues Dr. Barski used this approach to map more than 40 chromatin modifications in human T cells, which fundamentally improved the understanding of epigenetic regulation of transcription. Dr. Barski has since been using ChIP-Seq and other sequencing-based genome-wide methods to understand the role of chromatin modifications in gene regulation. His most recent work includes investigation of chromatin regulation of genes transcribed by RNA Polymerase III and the discovery of gene poising in T cells.
Since his arrival to Cincinnati Children’s Hospital Medical Center in 2011, Dr. Barski is utilizing ChIP-Seq, RNA-Seq and other cutting-edge approaches to understand epigenetic basis of T cell activation, memory and tolerance.
Barski A, Chepelev I, Liko D, Cuddapah S, Fleming AB, Birch J, Cui K, White RJ, Zhao K. Pol II and its associated epigenetic marks are present at Pol III-transcribed noncoding RNA genes. Nat Struct Mol Biol. 2010 May;17(5):629-34. Cuddapah S, Barski A, Zhao K. Epigenomics of T cell activation, differentiation, and memory. Curr Opin Immunol. 2010 Jun;22(3):341-7.
Cuddapah S, Barski A, Cui K, Schones DE, Wang Z, Wei G, Zhao K. Native chromatin preparation and Illumina/Solexa library construction. Cold Spring Harb Protoc. 2009 Jun;2009(6):pdb.prot5237. Barski A, Jothi R, Cuddapah S, Cui K, Roh TY, Schones DE, Zhao K. Chromatin poises miRNA- and protein-coding genes for expression. Genome Res. 2009 Oct;19(10):1742-51
Barski A, Zhao K. Genomic location analysis by ChIP-Seq. J Cell Biochem. 2009 May 1;107(1):11-8. Jothi R, Cuddapah S, Barski A, Cui K, Zhao K. Genome-wide identification of in vivo protein-DNA binding sites from ChIP-Seq data. Nucleic Acids Res. 2008 Sep;36(16):5221-31. Wang Z, Zang C, Rosenfeld JA, Schones DE, Barski A, Cuddapah S, Cui K, Roh TY, Peng W, Zhang MQ, Zhao K. Combinatorial patterns of histone acetylations and methylations in the human genome. Nat Genet. 2008 Jul;40(7):897-903 Schones DE, Cui K, Cuddapah S, Roh TY, Barski A, Wang Z, Wei G, Zhao K. Dynamic regulation of nucleosome positioning in the human genome. Cell. 2008 Mar 7;132(5):887-98. Barski A, Cuddapah S, Cui K, Roh TY, Schones DE, Wang Z, Wei G, Chepelev I, Zhao K. High-resolution profiling of histone methylations in the human genome. Cell. 2007 May 18;129(4):823-37. Barski A, Frenkel B. ChIP Display: novel method for identification of genomic targets of transcription factors. Nucleic Acids Res. 2004 Jul 13;32(12):e104.
Jorge A. Bezerra, MD Medical Director, Pediatric Liver Care Center
Medical Director, Pediatric Liver Care Center
Professor, UC Department of Pediatrics
Jorge A. Bezerra, MD, joined the Cincinnati Children's Hospital Medical Center Division of Gastroenterology, Hepatology and Nutrition in 1990, when he began his fellowship training in pediatric gastroenterology and nutrition and graduated in 1993.
From 1992-1994, Dr. Bezerra was a research scholar in the Division of Basic Sciences. He was appointed to the division in 1994 as an assistant professor of pediatrics.
Dr. Bezerra completed his residency in pediatrics at the University of Arizona in Tucson, Arizona.
Dr. Bezerra has an active research career with his primary interests in molecular control of liver regeneration, biliary atresia, and genetic basis of intrahepatic cholestasis.
In addition to his research work, Dr. Bezerra is an active clinician for the outpatient GI clinical service and the inpatient liver service.
MD: Federal University Rio Grande Norte, Natal, Brazil, 1984
Residency: University of Arizona, Tuscon, AZ, 1989
Fellowship: Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH, 1994
Certification: Pediatrics, Pediatric Gastroenterology, Hepatology and Nutrition
Bezerra JA. Biliary atresia in Brazil: where we are and where we are going. J Pediatr (Rio J). 2010 Nov-Dec;86(6):445-7. Moyer K, Kaimal V, Pacheco C, Mourya R, Xu H, Shivakumar P, Chakraborty R, Rao M, Magee JC, Bove K, Aronow BJ, Jegga AG, Bezerra JA. Staging of biliary atresia at diagnosis by molecular profiling of the liver. Genome Med. 2010 May 13;2(5):33.
Kumar Mohanty S, Ivantes CA, Mourya R, Pacheco C, Bezerra JA. Macrophages are targeted by rotavirus in experimental biliary atresia and induce neutrophil chemotaxis via Mip2/Cxcl2. Pediatr Res. 2010 Jan 6. Shivakumar P, Sabla GE, Whitington P, Chougnet CA, Bezerra JA. Neonatal NK cells target the mouse duct epithelium via Nkg2d and drive tissue-specific injury in experimental biliary atresia. J Clin Invest. 2009 Aug;119(8):2281-90. Shanmukhappa K, Matte U, Degen JL, Bezerra JA. Plasmin-mediated proteolysis is required for hepatocyte growth factor activation during liver repair. J Biol Chem. 2009 May 8;284(19):12917-23. Erickson N, Mohanty SK, Shivakumar P, Sabla G, Chakraborty R, Bezerra JA. Temporal-spatial activation of apoptosis and epithelial injury in murine experimental biliary atresia. Hepatology. 2008 May;47(5):1567-77. Shivakumar P, Sabla G, Mohanty S, McNeal M, Ward R, Stringer K, Caldwell C, Chougnet C, Bezerra JA. Effector role of neonatal hepatic CD8+ lymphocytes in epithelial injury and autoimmunity in experimental biliary atresia. Gastroenterology. 2007 Jul;133(1):268-77. Liu C, Aronow BJ, Jegga AG, Wang N, Miethke A, Mourya R, Bezerra JA. Novel resequencing chip customized to diagnose mutations in patients with inherited syndromes of intrahepatic cholestasis. Gastroenterology. 2007 Jan;132(1):119-26. Campbell KM, Arya G, Ryckman FC, Alonso M, Tiao G, Balistreri WF, Bezerra JA. High prevalence of alpha-1-antitrypsin heterozygosity in children with chronic liver disease. J Pediatr Gastroenterol Nutr. 2007 Jan;44(1):99-103. Shanmukhappa K, Sabla GE, Degen JL, Bezerra JA. Urokinase-type plasminogen activator supports liver repair independent of its cellular receptor. BMC Gastroenterol. 2006 Nov 29;6:40.
Charles C. Caldwell, PhD
focuses his research around trauma, sepsis and inflammation.
Associate Professor, UC Department of Surgery
BA: University of California, San Diego, CA.
PhD: San Diego State University, San Diego, CA.
Post-doctoral Studies: Laboratory of Immunology, NIAID, NIH
Jose A. Cancelas Perez, MD, PhD Division Director of Research, Hoxworth Blood Center
Division Director of Research, Hoxworth Blood Center
Deputy Director, Hoxworth Blood Center
Director, Research Flow Cytometry Core
Leader, Stem Cell Program
Medical Director of Cellular Therapies, Hoxworth Blood Center
Associate Professor, UC Department of Pediatrics
Hematopoietic stem cell proliferation and differentiation
Visit the Cancelas Lab.
MD: Autonomous University of Madrid, Spain, 1989.
Residency: Hematology and Hematotherapy, University of Alcala de Henares, Madrid, Spain, 1993.
PhD: Faculty of Medicine, University of Alcala de Henares, Madrid, Spain, 1996.
Dumont LJ*, Cancelas JA*, Graminske S, Friedman KD, Vassallo RR, Whitley PH, Rugg N, Dumont DF, Herschel L, Siegal AH, Szczepiorkowski ZM, Fender L, Razatos A. In vitro and in vivo quality of leukocyte-reduced apheresis platelets stored in a new platelet additive solution. Transfusion. 2012. (*both authors contributed equally).
Prada CE, Jousma E, Rizvi TA, Wu J, Dunn RS, Mayes DA, Cancelas JA, Dombi E, Kim MO, West BL, Bollag G, Ratner N. Neurofibroma-associated macrophages play roles in tumor growth and response to pharmacological inhibition. Acta Neuropathol. 2013 Jan;125(1):159-68.
Dumont LJ, Cancelas J, Dumont DF, Siegel AH, Szczepiorkowski ZM, Rugg R, Pratt PG, Worsham DN, Hartman EL, Dunn SK, O’Leary M, Ransom JH, Michael RA, Macdonald VW. A randomized controlled trial evaluating recovery and survival of 6% dimethyl sulfoxide-frozen autologous platelets in healthy volunteers. Transfusion. 2013 Jan;53(1):128-37.
Taniguchi Ishikawa E, Cancelas JA. Lack of communication rusts and ages stem cells. Cell Cycle. 2012 Sep 1;11(17):3149-3150.
Geiger H, Pawar SA, Kerschen EJ, Nattamai KJ, Hernandez I, Liang HP, Fernández JA, Cancelas JA, Ryan MA, Kustikova O, Schambach A, Fu Q, Wang J, Fink LM, Petersen KU, Zhou D, Griffin JH, Baum C, Weiler H, Hauer-Jensen M. Pharmacological targeting of the thrombomodulin-activated protein C pathway mitigates radiation toxicity. Nat Med. 2012 Jul;18(7):1123-9.
Chang KH, Sanchez-Aguilera A, Shen S, Sengupta A, Madhu MN, Ficker AM, Dunn SK, Kuenzi AM, Anrett JL, Santho RA, Agirre X, Perentesis JP, Deininger MW, Zheng Y, Bustelo XR, Williams DA, Cancelas JA. Vav3 collaborates with p190-BCR-ABL in lymphoid progenitor leukemogenesis, proliferation and survival. Blood. 2012 Jul 26;120(4):800-11.
Taniguchi Ishikawa E, Gonzalez-Nieto D, Ghiaur G, Dunn SK, Ficker AM, Murali B, Madhu M, Gutstein DE, Fishman GI, Barrio LC, Cancelas JA. Connexin-43 prevents hematopoietic stem cell senescence through transfer of reactive oxygen species to bone marrow stromal cells. Proc Natl Acad Sci USA. 2012 Jun 5;109(23):9071-6.
Konstantinidis DG, Pushkaran S, Johnson JF, Cancelas JA, Manganaris S, Harris CE, Williams DA, Zheng Y, Kalfa TA. Signaling and cytoskeletal requirements in erythroblast enucleation. Blood. 2012 Jun 21;119(25):6118-27.
Gonzalez-Nieto D, Li L, Köhler A, Ghiaur G, Ishikawa E, Sengupta A, Madhu M, Arnett J, Santho R, Dunn S, Fishman G, Gutstein D, Civitelli R, Barrio L, Gunzer M, Cancelas J. Connexin-43 in the osteogenic BM niche regulates its cellular composition and the bidirectional traffic of hematopoietic stem cells and progenitors. Blood. 2012 May 31;119(22):5144-54.
Sengupta A, Ficker A, Dunn S, Madhu M, Cancelas JA. Bmi1 reprograms chronic myelogenous leukemia B-lymphoid progenitors to become B-ALL-initiating cells. Blood. 2012 Jan 12;119(2):494-502.
Progenitor Cell Biology Consortium Administrative Coordinating Center, NHLBI/ Subaward through Univ. Maryland. Co-Director. (Cincinnati Cell Char Core). Sep 2010 – Aug 2016. #U01 HL099997.
Rational Design of a Vav/Rac Inhibitor as a New Therapy for High-Risk B-ALL. Principal Investigator. Leukemia & Lymphoma Society of North America. Oct 2012 – Sep 2015.
Cincinnati Excellence in Molecular Hematology: Cell Analysis and Sorting Core, NIH/NIDDK. Co-investigator. (Flow Cytometry Core Co-PI). Sep 2010 – Jun 2015. #P30DK090971-01.
Claire A. Chougnet, PhD
aims to understand T cell function and dysfunction at a molecular level in human disease, with a focus on defining the molecular mechanisms that underlie T cell dysfunction in HIV/AIDS, defining the molecular mechanisms responsible for immune dysfunction in aging, and understanding the development of T cell responses in very early life.
Antigen-presenting cells; HIV research; ontogeny of immune responses
HIV/AIDS pathogenesis; immune dysfunction in aging; ontogeny of immune system
DPharm:Université Paris XI, Paris, France, 1980.
CES (French specialized degrees; clinical biologist): Immunology, Hematology, Bacteriology-Virology, Parasitology, 1984.
PhD: Université Paris V, 1991.
Lages CS, Lewkowich I, Sproles A, Wills-Karp M, Chougnet C. Partial restoration of T-cell function in aged mice by in vitro blockade of the PD-1/ PD-L1 pathway. Aging Cell. 2010 Oct;9(5):785-98. doi: 10.1111/j.1474-9726.2010.00611.x. Miethke AG, Saxena V, Shivakumar P, Sabla GE, Simmons J, Chougnet CA. Post-natal paucity of regulatory T cells and control of NK cell activation in experimental biliary atresia. J Hepatol. 2010 May;52(5):718-26. Epub 2010 Mar 5. Presicce P, Moreno-Fernandez ME, Lages CS, Orsborn KI, Chougnet CA. Association of two clones allows for optimal detection of human FOXP3. Cytometry A. 2010 Jun;77(6):571-9. Moreno-Fernandez ME, Zapata W, Blackard JT, Franchini G, Chougnet CA. Human regulatory T cells are targets for human immunodeficiency Virus (HIV) infection, and their susceptibility differs depending on the HIV type 1 strain. J Virol. 2009 Dec;83(24):12925-33. Epub 2009 Oct 14.
Shivakumar P, Sabla GE, Whitington P, Chougnet CA, Bezerra JA. Neonatal NK cells target the duct epithelium via Nkg2d and drive the tissue-specific injury in biliary atresia. J Clin Invest. 2009 Aug;119(8)2281-90.
Nyakeriga AM, Fichtenbaum CJ, Goebel J, Nicolaou SA, Conforti L, Chougnet CA. Engagement of the CD4 receptor affects the redistribution of lck to the immunological synapse in primary T cells: implications for T cell activation during HIV-1 infection. J Virol. 2009 Feb;83(3):1193-200.
Boasso A, Shearer GM, Chougnet C. Immune dysregulation in HIV infection: know it, fix it, prevent it? J Intern Med. 2009, 265(1):78-96. Review.
Lages CS, Suffia I, Velilla P, Huang B, Warshaw G, Hildeman D, Belkaid Y, Chougnet C. Functional regulatory T cells accumulate in aged hosts and promote reactivation of chronic infectious disease reactivation. J Immunol. 2008;181(3):1835-48.
Velilla PA, Shata MT, Lages CS, Ying J, Fichtenbaum CJ, Chougnet C. Effect of intrauterine HIV-1 exposure on the frequency and phenotype of uninfected newborns’ dendritic cells. Clin Immunol. 2008;126:243-50.
Li S, Gowans EJ, Chougnet C, Plebanski M, Dittmer U. Natural regulatory T cells and persistent viral infection. J Virol. 2008;82:21-30. Review.
Jay L. Degen, PhD
Molecular genetics of plasminogen activation in development, hemostasis, and tumor progression; molecular genetics and biological role of plasminogen activation in development, hemostasis, wound repair, and disease
Jay L. Degen, PhD, is studying the regulation and biological roles of urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA), the two mammalian enzymes that convert plasminogen to the active serine protease, plasmin.
The PA/plasmin system of proteases is of particular interest because of its apparent dual function in the lysis of vascular fibrin clots (fibrinolysis) and the degradation of extracellular matrix in tissue remodeling and cell migration events.
Over the last few years, Dr. Degen's lab has generated and characterized gene-targeted mouse lines with deficits in the factors that are the foundation of the coagulation and fibrinolytic cascades, including fibrinogen-, plasminogen-, plasminogen activator-, and plasminogen activator receptor-deficient mouse lines.
These unique experimental animals are being intensively analyzed with regard to a wide range of phenotypic properties, including hemostasis, wound healing, angiogenesis and tumor biology.
Senad Divanovic, PhD
investigates the molecular mechanisms underlying the regulation of innate immune signaling and inflammation in: (a) development and progression of obesity; (b) development and progression of non-alcoholic fatty liver disease; and (b) induction of preterm birth. These studies, range from reductive analysis of TLR ligand signaling and challenge to the role of IL-17 axis to diverse experimental models of obesity and infection.
Innate immune responses; obesity; NAFLD; preterm birth
BA: DePauw University, Greencastle, IN, 1998.
MS: Oklahoma State University, Stillwater, OK, 2000. PhD: University of Cincinnati, Cincinnati, OH, 2005. Post Doc: Cincinnati Children’s Hospital Medical Center, 2010
Allen JL, Flick LM, Divanovic S, Jackson SW, Bram R, Rawlings D, Finkelman FD, Karp CL. Cutting Edge: Regulation of TLR4-driven B cell proliferation by RP105 is not B cell-autonomous. J Immunol. 2012;188:2065.
Korfhagen TR, Kitzmiller J, Chen G, Sridharan A, Haitchi HM, Hegde RS, Divanovic S, Karp CL, Whitsett JA. SAM-pointed domain ETS factor mediates epithelial cell-intrinsic innate immune signaling during airway mucous metaplasia. PNAS. 2012;109:16630.
Divanovic S, Sawtell NM, Trompette A, Warning JI, Dias A, Cooper AM, Yap GS, Arditi M, Shimada K, DuHadaway JB, Prendergast GC, Basaraba RJ, Mellor AL, Munn DH, Aliberti J, Karp CL. Opposing biological functions of tryptophan catabolizing enzymes during intracellular infection. J Infect Dis. 2012;205:152-61.
Divanovic S, Trompette A, Jamie I. Ashworth, Marepalli B. Rao, Karp CL. Therapeutic enhancement of protective immunity during experimental Leishmania major infection. PLoS Neglected Tropical Dis. 2011;5:e1316. Sheridan R, Lampe K, Shanmukhappa SK, Putnam P, Keddache M, Divanovic S, Bezerra J, Hoebe K. Lampe1: an ENU-germline mutation causing spontaneous hepatosteatosis identified through targeted exon-enrichment and next-generation sequencing. PLoS One. 2011;6:e21979. Trompette A, Divanovic S, Visintin A, Blanchard C, Hegde RS, Madan R, Torne PS, Wills-Karp M, Gioannini TL, Weiss JP, Karp CL. Allergenicity resulting from functional mimicry of a Toll-like receptor complex protein. Nature. 2009;457:585-8.
Divanovic S, Trompette A, Petiniot LK, Allen JL, Flick LM, Belkaid Y, Madan R, Haky JJ, Karp CL. Regulation of TLR4 signaling and the host interface with pathogens and danger: the role of RP105. J Leukocyte Biol. 2007;82:265-271. Divanovic S, Trompette A, Atabani SF, Madan R, Golenbock DT, Visintin A, Finberg RW, Tarakhovsky A, Vogel SN, Belkaid Y, Kurt-Jones EA, Karp CL. Inhibition of TLR4/MD-2 signaling by RP105/MD-1. J Endotoxin Res. 2005;11:363-8. Divanovic S, Trompette A, Atabani SF, Madan R, Golenbock DT, Visintin A, Finberg RW, Tarakhovsky A, Vogel SN, Belkaid Y, Kurt-Jones EA, Karp CL. Negative regulation of Toll-like receptor 4 signaling by the Toll-like receptor homolog RP105. Nature Immunol. 2005;6:571-8.
Divanovic S, Lai ACK. Cytokine induction in human cord blood lymphocytes after pulsing with UV-inactivated influenza viruses. Immunology Lett. 2004;94:201-7.
Marie-Dominique Filippi, PhD
Dr. Filippi is particularly interested in dissecting the molecular mechanism of hematopoietic cell migration, including neutrophils and hematopoietic stem cells in physiological settings. Migration is a critical function of hematopoietic cell in which actin cytoskeleton reorganization plays a central role. Because hematopoietic cells are utilized for the therapy of multiple blood diseases and neutrophils are responsible for maintaining an immunocompetence status, understanding the molecular mechanism of normal hematopoietic cell functions is of potential therapeutic importance. The small RHO GTPase family, members of the Ras superfamily, including Rac, RHO and CDC42, play key roles in regulating many of these functions. During her post-doc in the laboratory of Dr. David Williams, they have demonstrated that two highly related proteins, Rac1 and Rac2, of the small Rho GTPase family, have distinct functions in the control of hematopoietic cell functions. In particular in neutrophils, they have shown that both Rac1 and Rac2 regulate cell migration but with distinct mechanism (Gu and Filippi et al, Science 2003) both in vitro and in vivo. In addition to this work, they have dissected the sequence/determinant specificity of Rac2 versus Rac1 functions in neutrophils and demonstrated that Rac2 controls its functions, at least in part, by distinct subcellular distributions of these GTPases (Tao et al, Blood 2002, Filippi et al, Nat Immunol 2004), highlighting one important mechanism controlling cellular functions. Dr. Filippi's laboratory, in collaboration Dr. Yi Zheng, is now focused on determining the role of CDC42 and RhoA in neutrophil migration and in determining specifically the role of RhoA in hematopoietic stem cell migration and proliferation using gene targeted knock out mice for CDC42 and RhoA and their respective regulator CDC42GAP and 190RhoGAP. These studies will use in vitro and in vivo assays of cell migration as well as immunofluorescence microscopy to study cytoskeleton rearrangement associated with cell migration. The long term goal of these studies is to identify new molecular targets of potential therapeutic importance.
Visit the Filippi Lab.
Mulloy JC, Cancelas JA, Filippi MD, Kalfa TA, Guo F, Zheng Y. Rho GTPases in hematopoiesis and hemopathies. Blood. 2010 Feb 4;115(5):936-47. Szczur K, Zheng Y, Filippi MD. The small Rho GTPase Cdc42 regulates neutrophil polarity via CD11b integrin signaling. Blood. 2009 Nov 12;114(20):4527-37. Xu H, Eleswarapu S, Geiger H, Szczur K, Daria D, Zheng Y, Settleman J, Srour EF, Williams DA, Filippi MD. Loss of the Rho GTPase activating protein p190-B enhances hematopoietic stem cell engraftment potential. Blood. 2009 Oct 22;114(17):3557-66.Gu Y, Harley IT, Henderson LB, Aronow BJ, Vietor I, Huber LA, Harley JB, Kilpatrick JR, Langefeld CD, Williams AH, Jegga AG, Chen J, Wills-Karp M, Arshad SH, Ewart SL, Thio CL, Flick LM, Filippi MD, Grimes HL, Drumm ML, Cutting GR, Knowles MR, Karp CL. Identification of IFRD1 as a modifier gene for cystic fibrosis lung disease. Nature. 2009 Apr 23;458(7241):1039-42.
Monk KR, Wu J, Williams JP, Finney BA, Fitzgerald ME, Filippi MD, Ratner N. Mast cells can contribute to axon-glial dissociation and fibrosis in peripheral nerve. Neuron Glia Biol. 2007 Aug;3(3):233-44.
Daria D, Filippi MD, Knudsen ES, Faccio R, Li Z, Kalfa T, Geiger H. The retinoblastoma tumor suppressor is a critical intrinsic regulator for hematopoietic stem and progenitor cells under stress. Blood. 2008 Feb 15;111(4):1894-902. Uchida K, Beck DC, Yamamoto T, Berclaz PY, Abe S, Staudt MK, Carey BC, Filippi MD, Wert SE, Denson LA, Puchalski JT, Hauck DM, Trapnell BC. GM-CSF autoantibodies and neutrophil dysfunction in pulmonary alveolar proteinosis. N Engl J Med. 2007 Feb 8;356(6):567-79.Filippi MD, Szczur K, Harris CE, Berclaz PY. Rho GTPase Rac1 is critical for neutrophil migration into the lung. Blood. 2007 Feb 1;109(3):1257-64. Szczur K, Xu H, Atkinson S, Zheng Y, Filippi MD. Rho GTPase CDC42 regulates directionality and random movement via distinct MAPK pathways in neutrophils. Blood. 2006 Dec 15;108(13):4205-13.Wang L, Yang L, Filippi MD, Williams DA, Zheng Y. Genetic deletion of Cdc42GAP reveals a role of Cdc42 in erythropoiesis and hematopoietic stem/progenitor cell survival, adhesion, and engraftment. Blood. 2006 Jan 1;107(1):98-105.
Fred Finkelman, MD
is interested in the use of in vivo mouse models to study both basic immunology and disease pathogenesis. More specifically, he is trying to understand how cytokines and other immune mechanisms control intestinal worms infections; allergic, asthmatic, and anaphylactic diseases; as well as T cell memory.
Rheumatology; cytokine control of immune-mediated disorders and host protection against parasites, cytokine regulation of allergic disorders, cytokine regulation of lymphopoiesis; regulation of cytokine responses and mechanisms of lymphocyte activation and tolerance; anaphylaxis; transfusion-related acute lung injury
Khodoun MV, Strait R, Armstrong L, Yanase N, Finkelman FD. Identification of markers that distinguish IgE- from IgG-mediated anaphylaxis. Proc Natl Acad Sci U S A. 2011 Jul 26;108(30):12413-8.
Strait RT, Mahler A, Hogan S, Khodoun M, Shibuya A, Finkelman FD. Ingested allergens must be absorbed systemically to induce systemic anaphylaxis. J Allergy Clin Immunol. 2011 Apr;127(4):982-9.e1.
Perkins C, Yanase N, Smulian G, Gildea L, Orekov T, Potter C, Brombacher F, Aronow B, Wills-Karp M, Finkelman FD. Selective stimulation of IL-4 receptor on smooth muscle induces airway hyperresponsiveness in mice. J Exp Med. 2011 Apr 11;208(4):853-67.
Brandt EB, Munitz A, Orekov T, Mingler MK, McBride M, Finkelman FD, Rothenberg ME. Targeting IL-4/IL-13 signaling to alleviate oral allergen-induced diarrhea. J Allergy Clin Immunol. 2009 Jan;123(1):53-8.
Herbert Herbert DR, Orekov T, Roloson A, Ilies M, Perkins C, O'Brien W, Cederbaum S, Christianson DW, Zimmermann N, Rothenberg ME, Finkelman FD. Arginase I suppresses IL-12/IL-23p40-driven intestinal inflammation during acute schistosomiasis. J Immunol. 2010 Jun 1;184(11):6438-46.
DR, Yang JQ, Hogan SP, Groschwitz K, Khodoun M, Munitz A, Orekov T, Perkins C, Wang Q, Brombacher F, Urban JF Jr, Rothenberg ME, Finkelman FD. Intestinal epithelial cell secretion of RELM-beta protects against gastrointestinal worm infection. J Exp Med. 2009 Dec 21;206(13):2947-57.
Morris SC, Heidorn SM, Herbert DR, Perkins C, Hildeman DA, Khodoun MV, Finkelman FD. Endogenously produced IL-4 nonredundantly stimulates CD8+ T cell proliferation. J Immunol. 2009 Feb 1;182(3):1429-38. Khodoun M, Strait R, Orekov T, Hogan S, Karasuyama H, Herbert DR, Köhl J, Finkelman FD. Peanuts can contribute to anaphylactic shock by activating complement. J Allergy Clin Immunol. 2009 Feb;123(2):342-51.Forbes EE, Groschwitz K, Abonia JP, Brandt EB, Cohen E, Blanchard C, Ahrens R, Seidu L, McKenzie A, Strait R, Finkelman FD, Foster PS, Matthaei KI, Rothenberg ME, Hogan SP. IL-9- and mast cell-mediated intestinal permeability predisposes to oral antigen hypersensitivity. J Exp Med. 2008 Apr 14;205(4):897-913. Phelan JD, Orekov T, Finkelman FD. Cutting edge: mechanism of enhancement of in vivo cytokine effects by anti-cytokine monoclonal antibodies. J Immunol. 2008 Jan 1;180(1):44-8.
Matthew J. Flick, PhD
is working to understand how hemostatic factors in the blood that are responsible for clotting also drive inflammation in the context of infection and diseases such as arthritis and fatty liver disease.
Hemostatic factors and arthritis pathogenesis
Research Interests and Focus:
1. Activation of the coagulation system, including the central coagulation protease thrombin, is a prominent feature of both human rheumatoid arthritis and experimental inflammatory arthritis. The long-term goal of Dr. Flick's research program is to determine how thrombin drives inflammatory joint disease. The proposed work will fill significant gaps in the understanding of the interplay between the thrombin- fibrinogen axis and arthritic disease, and may provide the proof-of-principle for the use of novel "customized" thrombin mutants with selected substrate specificity to treat arthritis.
2. The pervasive gram-positive bacteria Staphylococcus aureus is a common pathogen that is the causative agent for a wide spectrum of diseases including skin infections, pneumonia, bacteremia, toxic-shock syndrome and sepsis. Notably, this pathogen has evolved and maintained a number of proteins that directly engage the host hemostatic system, including factors that directly interact with the host coagulation factor fibrinogen. The long-term goal of his research program is to understand how bacterial derived proteins interact with host factors to promote bacterial virulence in the context of blood-born infections. This work will provide novel insight into the molecular pathways by which S. aureus invades and disseminates within host tissues and may shed light into novel strategies for eliminating this potentially devastating infectious agent.
3. Obesity is a worldwide epidemic linked to numerous disease sequelae, including non-alcoholic fatty liver disease (NAFLD). This spectrum disorder can progress from the simple accumulation of triglycerides within hepatocytes (i.e., steatosis), to inflammatory steatohepatitis, to organ failure secondary to irreversible liver fibrosis and cirrhosis. Dysregulation of the coagulation system has been documented in both patients with fatty liver disease and animal models of NAFLD, but any contribution to disease progression has remained largely undefined. Using a murine model of high fat diet (HFD)-induced NAFLD, they are testing the hypothesis that thrombin activity and fibrin deposition drive local inflammatory events promoting the progression of steatosis and steatohepatitis. Comparative studies of wild-type mice with genetically imposed deficiencies or functional alterations in prothrombin, fibrinogen and other associated coagulation factor components suggests that the thrombin-fibrinogen axis influences NAFLD pathogenesis by controlling local inflammatory processes that drive steatosis and by an unanticipated and unknown mechanism tying fibrin(ogen) to HFD-induced weight gain/obesity. Their research has far-reaching implications not only for the treatment and prevention of fatty liver disease, but also for all the downstream sequelae of obesity and even the development of diet-mediated weight gain itself.
BS: Xavier University, Cincinnati, OH.
PhD: Purdue University, West Lafayette, IN.
Post-doctoral Fellow: Cincinnati Children’s Hospital and Medical Center, Division of Developmental Biology, Cincinnati, OH.
Flick MJ, Du X, Prasad JM, Raghu H, Palumbo JS, Smeds E, Höök M, Degen JL. Genetic elimination of the binding motif on fibrinogen for the S. aureus virulence factor ClfA improves host survival in septicemia. Blood. 2013 Jan 8.
Sullivan BP, Kassel KM, Jone A, Flick MJ, Luyendyk JP. Fibrin(ogen)-independent role of plasminogen activators in acetaminophen-induced liver injury. American Journal of Pathology. 2012;180(6):2321-2329.
Qi X, Flick MJ, Frederick M, Chu Z, Mason R, DeLay M, Thornton S. Saposin C Coupled Lipid Nanovesicles Specifically Target Arthritic Mouse Joints for Optical Imaging of Disease Severity. PLoSOne. 2012;7(3):e33966.
Vidal B, Ardite E, Suelves M, Ruiz-Bonilla V, Janué A, Flick MJ, Degen JL, Serrano AL, Muñoz-Cánoves P. Amelioration of Duchenne muscular dystrophy in mdx mice by elimination of matrix-associated fibrin-driven inflammation coupled to the αMβ2 leukocyte integrin receptor. Human Molecular Genetics. 2012;21(9):1989-2004.
Horowitz NA, Blevins EA, Miller WM, Perry AR, Talmage KE, Mullins ES, Flick MJ, Queiroz KC, Shi K, Spek CA, Conway EM, Monia BP, Weiler H, Degen JL, Palumbo JS. Thrombomodulin is a determinant of metastasis through a mechanism linked to the thrombin binding domain but not the lectin-like domain. Blood. 2011 Jul 25.
Raghu H, Flick MJ. Targeting the Coagulation Factor Fibrinogen for Arthritis Therapy. Curr Pharm Biotechnol. 2011 Mar 14.
Flick MJ, Chauhan AK, Frederick M, Talmage KE, Kombrinck KW, Miller W, Mullins ES, Palumbo JS, Zheng X, Esmon NL, Esmon CT, Thornton S, Becker A, Pelc LA, Di Cera E, Wagner DD, Degen JL. The development of inflammatory joint disease is attenuated in mice expressing the anticoagulant prothrombin mutant W215A/E217A. Blood. 2011 Jun 9;117(23):6326-37.
Steinbrecher KA, Horowitz NA, Blevins EA, Barney KA, Shaw MA, Harmel-Laws E, Finkelman FD, Flick MJ, Pinkerton MD, Talmage KE, Kombrinck KW, Witte DP, Palumbo JS. Colitis-associated cancer is dependent on the interplay between the hemostatic and inflammatory systems and supported by integrin alpha(M)beta(2) engagement of fibrinogen. Cancer Res. 2010 Apr 1;70(7):2634-43.
Mullins ES, Kombrinck KW, Talmage KE, Shaw MA, Witte DP, Ullman JM, Degen SJ, Sun W, Flick MJ, Degen JL. Genetic elimination of prothrombin in adult mice is not compatible with survival and results in spontaneous hemorrhagic events in both heart and brain. Blood. 2009 Jan 15;113(3):696-704.
Mechanisms linking the hemostatic protease thrombin to arthritic disease. Principal Investigator. National Institute of Arthritis and Musculoskeletal and Skin Diseases. Jul 2009-Jun 2014. #R01 AR056990.
Thrombin-mediated proteolysis in neuroinflammatory disease. Co-investigator. National Heart, Lung, and Blood Institute. Jul 2009-Jun 2014. #R01 HL096126.
NIH, National Institute of Arthritis and Musculoskeletal and Skin Diseases Research. Director. Cincinnati Rheumatic Diseases Core Center. Aug 2011-Jun 2016. 2P30 AR47363.
Hemostatic factors and sickle cell disease. Co-investigator. NIH. Dec 2011-Nov 2016. R01 HLI12603.
Analysis of Staphylococcus Host Interactions. Co-investigator. NIH. Sep 2010-Aug 2015. R01 AI020662.
H. Leighton (Lee) Grimes, PhD Director, Cancer Pathology Program of the Division of Experimental Hematology and the Division of Pathology
Director, Cancer Pathology Program of the Division of Experimental Hematology and the Division of Pathology
Co-Leader, Program in Hematologic Malignancies of Cincinnati Children's Hospital Medical Center, Cancer and Blood Diseases Institute
Transcriptional control of hematopoiesis and cancer.
Visit the Grimes Lab.
The cloning and characterization of oncoproteins and tumor suppressors over the last 25 years has not only resulted in a greater understanding of the molecular mechanisms of transformation, but it has also provided a large set of therapeutic targets. Our lab is interested in the progression of a cell with a single genetic lesion to an invasive cancer with multiple genetic alterations. We focus on the Growth factor independence-1 (Gfi1) transcription factor, which is poorly oncogenic alone, but which potently collaborates with well known oncoproteins such as c-MYC. Gfi1 is the most frequently targeted gene in Moloney murine leukemia virus-induced tumors and induces tumor progression to cytokine-independent growth. In contrast, loss of Gfi1 in hematopoietic stem cells induces cell cycle progression and eventual bone marrow failure; implicating Gfi1 as a tumor suppressor in such cells. Gfi1 null mice have no mature neutrophils, and we have identified humans with Severe Congenital Neutropenia (SCN) and Non-Immune Chronic Idiopathic Neutropenia of Adults (NI-CINA) bearing mutations in Gfi1. Interestingly, such patients are at increased risk for the development of myelodysplastic syndromes and acute myeloid leukemia. We have recently generated the first mouse model of Severe Congenital Neutropenia through the expression of mutant Gfi1 proteins in primary murine hematopoietic cells. Moreover, we are utilizing mouse models of human cancer to assess the risk of Gfi1 mutant humans for the development of acute myeloid leukemia.
Phelan JD, Saba AI, Olsson A, Zeng H, Kosan C, Messer MS, Hildeman D, Aronow B, Möröy T, Grimes HL. Growth factor independent-1 maintains Notch1-dependent transcriptional programming of lymphoid precursors. PLoS Genetics. 2013. In press.
Khandanpour C*, Phelan JD*, Vassen L, Schutte J, Chen R, Horman SR, Gaudreau MC, Krongold J, Zhu J, Paul WE, Duhrsen U, Gottgens B, Grimes HL# Moroy T#. Growth factor independence 1 (Gfi1) antagonizes a p53-induced DNA damage response pathway in lymphoblastic leukemia. Cancer Cell. 2013 Feb 11;23(2):200-14. * equal first author, # shared corresponding author.
Meyer SE, Hasenstein JR, Baktula A, Velu CS, Xu Y, Wan H, Whitsett JA, Gilks CB, Grimes HL. Kruppel-like factor 5 is not required for K-RasG12D lung tumorigenesis, but represses ABCG2 expression and is associated with better disease-specific survival. Am J Pathol. 2010 Sep;177(3):1503-13.
Horman SR, Velu CS, Chaubey A, Bourdeau T, Zhu J, Paul WE, Gebelein B, Grimes HL. Gfi1 integrates progenitor versus granulocytic transcriptional programming. Blood. 2009 May 28;113(22):5466-75.
Velu CS, Baktula AM, Grimes HL. Gfi1 regulates miR-21 and miR-196b to control myelopoiesis. Blood. 2009 May 7;113(19):4720-8.
Horman SR, Velu CS, Chaubey A, Bourdeau T, Zhu J, Paul WE, Gebelein B, Grimes HL. Gfi1 integrates progenitor versus granulocytic transcriptional programming. Blood. 2009 May 28;113(22):5466-75.
Gu Y, Harley IT, Henderson LB, Aronow BJ, Vietor I, Huber LA, Harley JB, Kilpatrick JR, Langefeld CD, Williams AH, Jegga AG, Chen J, Wills-Karp M, Arshad SH, Ewart SL, Thio CL, Flick LM, Filippi MD, Grimes HL, Drumm ML, Cutting GR, Knowles MR, Karp CL. Identification of IFRD1 as a modifier gene for cystic fibrosis lung disease. Nature. 2009 Apr 23;458(7241):1039-42.
Li-Kroeger D, Witt LM, Grimes HL, Cook TA, Gebelein B. Hox and senseless antagonism functions as a molecular switch to regulate EGF secretion in the Drosophila PNS. Dev Cell. 2008 Aug;15(2):298-308.
Zarebski1 A, Velu CS, Baktula AM, Bourdeau T, Horman SR, Basu S, Bertolone SJ, Horwitz M, Hildeman DA, Trent JO, Grimes HL. The Human Severe Congenital Neutropenia-Associated Gfi1N382S Mutant Blocks Murine Granulopoiesis Through CSF1. Immunity. 2008 Mar;28(3):370-80.
Person RE, Li FQ, Duan Z, Benson KF, Wechsler J, Papadaki HA, Eliopoulos G, Kaufman C, Bertolone SJ, Nakamoto B, Papayannopoulou T, Grimes HL, Horwitz M. Gfi1 Proto-Oncogene Mutation Causes Human Neutropenia and Targets Neutrophil Elastase. Nature Genetics. 2003 March 1;30: 295 - 300.
John B. Harley, MD, PhD Director, CAGE
is a rheumatologist and biochemist with special clinical and research interests in the genetic etiology of inflammatory diseases. His experimental focus is the many genetic effects and environmental causes of systemic lupus erythematosus (SLE) and related inflammatory diseases. Through this work, nearly 50 genes are known and Epstein Barr virus has been identified to trigger the systemic autoimmunity of lupus. Dr. Harley also builds infrastructure with which to do high throughput genotyping, expression analysis, and epigenetics, which he makes available to his colleagues from around the world. In recent experiments, Dr. Harley organized the logistics of managing >18,000 subjects at >30,000 genetic markers, 3200 subjects at 1.2 million markers, and 10,000 subjects at 196,000 markers. Dr. Harley is committed to all of the steps between association detection through replication and toward identifying the possible functional genetic variants and to pursuing their biology.
Cobb BL, Fei Y, Jonsson R, Bolstad AI, Brun JG, Rischmueller M, Lester SE, Witte T, Illei G, Brennan M, Bowman S, Moser KL, Harley JB, Sawalha AH. Genetic association between methyl-CpG binding protein 2 (MECP2) and primary Sjögren’s syndrome. Ann Rheum Dis. 2010; 69(9): 1731-2.Kim-Howard X, Maiti AK, Anaya J-M, Bruner GR, Brown E, Merrill JT, Edberg JC, Petri MA, Reveille JD, Ramsey-Goldman R, Alarcon GS, Vyse TJ, Gilkeson G, Kimberly RP, James JA, Guthridge JM, Harley JB, Nath SK. ITGAM coding variant (rs1143679) influences the risk of renal disease, discoid rash, and immunologic manifestations in lupus patients with European ancestry. Ann Rheum Dis. 2010.Javierre BM, Fernandez AF, Richter J, Al-Shahrour F, Martin-Subero JI, Rodriguez-Ubreva J, Berdasco M, Fraga MF, O'Hanlon TP, Rider LG, Jacinto FV, Lopez-Longo FJ, Dopazo J, Forn M, Peinado MA, Carreno L, Sawalha AH, Harley JB, Siebert R, Esteller M, Miller FW, Ballestar E. Changes in the pattern of DNA methylation associate with twin discordance in systemic lupus erythematosus. Genome Res. 2010; 20(2):170-179. Harley JB, James JA. Everyone comes from somewhere: systemic lupus erythematosus and Epstein-Barr virus, induction of host interferon (INF) and humoral anti-EBNA1 immunity. Arthritis Rheum. 2010.\Bronson PG, Komorowski LK, Ramsay PP, May SL, Noble J, Lane JA, Thomson G, Claas FH, Seldin MF, Kelly JA, Harley JB, Moser KL, Gaffney PM, Behrens T, Criswell LA, Barcellos LF. Analysis of maternal-offspring HLA compatibility, parent-of-origin and noninherited effects for HLA-DRB1 in systemic lupus erythematosus. Arthritis Rheum. 2010.Heinlen LD, McClain MT, Ritterhouse LL, Bruner BF, Edgerton CC, Keith MP, James JA, Harley JB. 60kD Ro and nRNP A frequently initiate human lupus autoimmunity. PLoS ONE. 2010 5(3):e9599.
Sammalisto S, Hiekkalinna T, Schwander K, Kardia S, Weder AB, Rodriquez BL, Doria A, Kelly JA, Bruner GR, Harley JB, Redline S, Larkin EK, Patel SR, Ewan AJ, Weber JL, Perola M, Peltonen L. Genome-wide linkage screen for stature and body mass index in 3.032 families: evidence for sex-and population-specific genetic effects. Eur J Hum Genet. 2009 Jan 1;17(2):258-266.
Poole BD, Templeton AK, Guthridge JM, Brown EJ, Harley JB, James JA. Aberrant Epstein-Barr viral infection in systemic lupus erythematosus. Autoimmun Rev. 2009 Feb;8(4):337-42. Poole BD, Schneider RI, Guthridge JM, Velte CA, Reichlin M, Harley JB, James JA. Early targets of nuclear RNP humoral autoimmunity in human systemic lupus erythematosus. Arthritis Rheum. 2009 Feb 26; 60(3):848-859. Han S, Kim-Howard X, Deshmukh H, Kamatani Y, Viswanathan P, Guthridge JM, Thomas K, Kaufman KM, Ojwang J, Rojas-Villarraga A, Baca V, Orozco L, Rhodes B, Choi CB, Gregersen PK, Merrill JT, James JA, Gaffney PM, Moser KL, Jacob CO, Kimberly RP, Harley JB, Bae SC, Anaya JM, Alarcon-Riquelme ME, Matsuda K, Vyse TJ, Nath SK. Evaluation of imputation-based association in and around the Integrin-α-M (ITGAM) gene and replication of robust association between a non-synonymous functional variant within ITGAM and systemic lupus erythematosus (SLE). Hum Mol Genet. 2009 Mar 15;18(6):1171-80.
Gurjit Khurana Hershey, MD, PhD Director, Division of Asthma Research
is the principal investigator of a federally funded Asthma and Allergic Diseases Cooperative Research Center which supports, in part, the asthma and allergy-based Greater Cincinnati Pediatric Clinic Repository. She also focuses on elucidating the genetic and environmental factors that contribute to the development of asthma and eczema.
Visit the Khurana Hershey Lab.
Director, Division of Asthma Research
Co-Director, Office of Pediatric Clinical Fellowships
Asthma; allergic rhinitis; food allergy; urticaria
Genetics of allergy and asthma; cytokines; signaling pathways
Gurjit Khurana Hershey, MD, PhD, received a BS degree from the University of Iowa, and MD and PhD degrees from Washington University School of Medicine. After completing pediatric residency and an allergy/immunology Fellowship at St. Louis Children’s Hospital, Dr. Khurana Hershey joined the faculty at Cincinnati Children’s Hospital Medical Center. She now directs the Division of Asthma Research at Cincinnati Children’s Hospital Medical Center and is the director of the Medical Scientist Training Program at the University of Cincinnati College of Medicine.
In addition to her clinical duties, Dr. Khurana Hershey directs an NIH-funded research program focused on the genetics and genomics of allergic inflammation with a focus on cytokines and signal transduction. Her research has been continuously funded for over fifteen years. She is the principal investigator of an NIH-funded Asthma and Allergic Diseases Cooperative Research Center (AADCRC), and is also the PI of the Inner City Asthma Consortium, an NIH funded subcontract. She is the PI of the UC T32 MSTP training grant. In addition to her research contributions, she is an outstanding clinician and teacher/mentor. Several of her trainees now hold academic faculty positions. She is the recipient of the 2013 Cincinnati Children’s Educational Achievement Award.
Dr. Khurana Hershey is a fellow of the American Pediatric Society and the American Academy of Allergy, Asthma and Immunology. She serves on the Executive Council of the American Academy of Asthma, Allergy and Immunology Program Committee, is the Chair of the Grant Review Committee and appointed Vice Chair of the Basic and Immunology Interest Section. She is a member of the Editorial Board of the Journal of Allergy and Clinical Immunology. She was recently named One of the Five Leading Women in Healthcare in the Greater Cincinnati Metropolitan Area, and Outstanding Woman at Cincinnati Children’s Hospital Medical Center.
BS: University of Iowa, Iowa City, IA, 1985.PhD: Washington University School of Medicine, St. Louis, MO, 1990.
MD: Washington University School of Medicine, St. Louis, MO, 1992. Residency: St. Louis Children's Hospital, St. Louis, MO, 1992-1995. Fellowship: St. Louis Children's Hospital, St. Louis, MO, 1995-1997.
Board Certification: American Board of Pediatrics, 2009 - Present.
Board Certification: American Board of Allergy and Immunology, 2008 - Present.
Biagini Myers JM, Martin LJ, Butsch Kovacic M, Mersha TB, He H, Pilipenko V, Lindsey MA, Ericksen MB, Bernstein DI, LeMasters GK, Lockey JE, Khurana Hershey GK. Epistasis between serine protease inhibitor Kazal-type 5 (SPINK5) and thymic stromal lymphopoietin (TSLP) genes contributes to childhood asthma. J Allergy Clin Immunol. 2014 May 13. pii: S0091-6749(14)00520-X.
Wood RA, Togias A, Wildfire J, Visness CM, Matsui EC, Gruchalla R, Hershey G, Liu AH, O’Connor GT, Pongracic JA, Zoratti E, Little F, Granada M, Kennedy S, Durham SR, Shamji MH, Busse WW. Development of cockroach immunotherapy by the Inner-City Asthma Consortium. J Allergy Clin Immunol. 2014 Mar;133(3)846-52.
Zhang Z, Xiao C, Gibson AM, Bass SA, Khurana Hershey GK. EGFR signaling blunts allergen-induced IL-6 production and Th17 responses in the skin and attenuates development and relapse of atopic dermatitis. J Immunol. 2014 Feb 1:192(3):859-66.
Kinker KG, Gibson AM, Bass SA, Day BP, Deng, J, Medvedovic M, Figueroa JA, Hershey GK, Chen W. Overexpression of dimethylarginine dimethylaminohydrolase 1 attenuates airway inflammation in a mouse model of asthma. PloS One. 2014 Jan 10;9 (1):e85148.
Acciani TH, Brandt EB, Khurana Hershey GK, Le Cras TD. Diesel exhaust particle exposure increases severity of allergic asthma in young mice and children. Clin Exp Allergy. 2013 Dec;43(12):1406-18.
Brandt EB, Kovacic MB, Lee GB, Gibson AM, Acciani TH, Le Cras TD, Budelsky AL, Khurana Hershey GK. Diesel exhaust particle induction of IL17A contributes to severe asthma. J Allergy Clin Immunol. 2013 Nov:132(5);1194-1204.
Brandt EB, Gibson AM, Bass S, Khurana Hershey GK. Exacerbation of Allergen-Induced Eczema in TLR4- and TRIF-Deficient Mice. J Immunol. 2013 Oct 1;191(7):3519-25.
Chen W, Sivaprasad U, Gibson AM, Ericksen MB, Cunningham CM, Bass SA, Kinker KG, Finkelman FD, Wills-Karp M, Khurana Hershey GK. IL-13 receptor α2 contributes to development of experimental allergic asthma. J Allergy Clin Immunol. 2013 Oct;132(4):951-958.
Lee GB, Brandt EB, Xiao C, Gibson AM, Le Cras TD, Brown LA, Fitzpatrick AM, Khurana Hershey GK. Diesel exhaust particles induce cysteine oxidation and S-glutathionylation in house dust mite induced murine asthma. PLoS One. 2013;8(3):e60632.
Mintz-Cole RA, Brandt EB, Bass SA, Gibson AM, Reponen T, Khurana Hershey GK. Surface availability of beta-glucans is critical determinant of host immune response to C. cladosporioides. J Allergy Clin Immunol. 2013 Jul;132(1):159-69.
David A. Hildeman, PhD Director, Immunology Graduate Program
explores the molecular factors that control the decision between tolerance and immunity within T lymphocytes. Using genetic mouse models, viruses, and MHC tetrameric reagents, the lab is focused on the molecular regulation of antigen-specific T cell responses. Dr. Hildeman is also the current director of the Immunology Graduate Program.
Director, Immunology Graduate Program
T cells; autoimmunity; sex differences in immune responses; apoptosis
Our lab is primarily interested in molecular factors that control the decision between tolerance and immunity within T lymphocytes. We use staphylococcal enterotoxins, recombinant vaccinia viruses, lymphocytic choriomeningitis virus and MHC tetrameric reagents as tools to study antigen -specific T cell responses. Our interest in tolerance centers on regulation of mechanisms that control the survival and death of activated T cells in vivo, namely Bcl-2 and its antagonist Bim. We are also interested in the manipulation and regulation of antigen-specific T cell responses via novel vaccine strategies to either induce tolerance or enhance immunity. Finally, we are interested in mechanisms underlying sex-based differences in T cell responses and how these differences relate to autoimmune disease.
Chae HD, Siefring JE, Hildeman DA, Gu Y, Williams DA. RhoH regulates subcellular localization of ZAP-70 and Lck in T cell receptor signaling. PLoS One. 2010 Nov 12;5(11):e13970.
Chougnet CA, Tripathi P, Lages CS, Raynor J, Sholl A, Fink P, Plas DR, Hildeman DA. A major role for Bim in regulatory T cell homeostasis. J Immunol. 2011 Jan 1;186(1):156-63.
Guo F, Hildeman D, Tripathi P, Velu CS, Grimes HL, Zheng Y. Coordination of IL-7 receptor and T-cell receptor signaling by cell-division cycle 42 in T-cell homeostasis. Proc Natl Acad Sci U S A. 2010 Oct 26;107(43):18505-10.
Kasten KR, Prakash PS, Unsinger J, Goetzman HS, England LG, Cave CM, Seitz AP, Mazuski CN, Zhou TT, Morre M, Hotchkiss RS, Hildeman DA, Caldwell CC. Interleukin-7 (IL-7) treatment accelerates neutrophil recruitment through gamma delta T-cell IL-17 production in a murine model of sepsis. Infect Immun. 2010 Nov;78(11):4714-22.
Tripathi P, Kurtulus S, Wojciechowski S, Sholl A, Hoebe K, Morris SC, Finkelman FD, Grimes HL, Hildeman DA. STAT5 is critical to maintain effector CD8+ T cell responses. J Immunol. 2010 Aug 15;185(4):2116-24.
Kurtulus S, Tripathi P, Opferman JT, Hildeman DA. Contracting the 'mus cells' -- does down-sizing suit us for diving into the memory pool? Immunol Rev. 2010 Jul;236:54-67. Review.
Lin AA, Wojciechowski SE, Hildeman DA. Androgens suppress antigen-specific T cell responses and IFN-γ production during intracranial LCMV infection. J Neuroimmunol. 2010 Sep 14;226(1-2):8-19.
Kasten KR, Tschöp J, Goetzman HS, England LG, Dattilo JR, Cave CM, Seitz AP, Hildeman DA, Caldwell CC. T-cell activation differentially mediates the host response to sepsis. Shock. 2010 Oct;34(4):377-83.
Kasten KR, Tschöp J, Adediran SG, Hildeman DA, Caldwell CC. T cells are potent early mediators of the host response to sepsis. Shock. 2010 Oct;34(4):327-36. Review.
Madan R, Demircik F, Surianarayanan S, Allen JL, Divanovic S, Trompette A, Yogev N, Gu Y, Khodoun M, Hildeman D, Boespflug N, Fogolin MB, Gröbe L, Greweling M, Finkelman FD, Cardin R, Mohrs M, Müller W, Waisman A, Roers A, Karp CL. Nonredundant roles for B cell-derived IL-10 in immune counter-regulation. J Immunol. 2009 Aug 15;183(4):2312-20.
Kasper Hoebe, PhD
focuses on mechanistic analysis of pathways of innate immune activation and the mechanisms underlying NK cell and CD8+ T cell development and cytolytic effector function, using forward genetic approaches. His discovery of an “endogenous adjuvant” pathway mediated by NK cell killing has led to research aimed at exploiting the knowledge obtained on NK cell-driven adaptive immune responses for the generation of new, safer vaccine approaches.
Innate-adaptive connection; mechanisms underlying NK cell and CD8+ T cell development; cytolytic effector function; safer vaccine approaches
Barnes MJ, Aksoylar H, Krebs P, Bourdeau T, Arnold CN, Xia Y, Khovananth K, Engel I, Sovath S, Lampe K, Laws E, Saunders A, Butcher GW, Kronenberg M, Steinbrecher K, Hildeman D, Grimes HL, Beutler B, Hoebe K. Loss of T cell and B cell quiescence precedes the onset of microbial flora-dependent wasting disease and intestinal inflammation in Gimap5-deficient mice. J Immunol. 2010 Apr 1;184(7):3743-54.
Krebs P, Barnes MJ, Lampe K, Whitley K, Bahjat KS, Beutler B, Janssen E, Hoebe K. NK-cell-mediated killing of target cells triggers robust antigen-specific T-cell-mediated and humoral responses. Blood. 2009 Jun 25;113(26):6593-602.
Hoebe K, Beutler B. Forward genetic analysis of TLR-signaling pathways: An evaluation. Adv Drug Deliv Rev. 2008 Apr 29;60(7):824-9.
Rutschmann S, Hoebe K. Dissecting innate immunity by germline mutagenesis. Immunology. 2008;123(4):459-68.
Baccala R, Hoebe K, Kono DH, Beutler B, Theofilopoulos AN. TLR-dependent and TLR-independent pathways of type I interferon induction in systemic autoimmunity. Nature Med. 2007;13(5);543–51.
Brinkmann MM, Spooner E, Hoebe K, Beutler B, Ploegh HL, Kim YM. The interaction between the ER membrane protein UNC93B and TLR3, 7, and 9 is crucial for TLR signaling. J Cell Biol. 2007;177(2):265-75.
Crozat K, Hoebe K, Ugolini S, Hong NA, Janssen E, Rutschmann S, Mudd S, Sovath S, Vivier E, Beutler B. Jinx, an MCMV susceptibility phenotype caused by disruption of Unc13d: a mouse model of type 3 familial hemophagocytic lymphohistiocytosis. J Exp Med. 2007;204(4):853-63.
Gavin AL, Hoebe K, Duong B, Ota T, Martin C, Beutler B, Nemazee D. Adjuvant-enhanced antibody responses in the absence of toll-like receptor signaling. Science. 2006;314(5807):1936-8.
Casrouge A, Zhang SY, Eidenschenk C, Jouanguy E, Puel A, Yang K, Alcais A, Picard C, Mahfoufi N, Nicolas N, Lorenzo L, Plancoulaine S, Senechal B, Geissmann F, Tabeta K, Hoebe K, Du X, Miller RL, Heron B, Mignot C, de Villemeur TB, Lebon P, Dulac O, Rozenberg F, Beutler B, Tardieu M, Abel L, Casanova JL. Herpes simplex virus encephalitis in human UNC-93B deficiency. Science. 2006;314(5797): 308-12.
Simon P. Hogan, PhD Director of Research, Division of Allergy and Immunology
Director of Research, Division of Allergy and Immunology
Director of Admissions, Immunology Graduate Program
Food allergies and anaphylaxis; inflammatory bowel diseases (IBD); innate immunity; gastrointestinal immunity and function; cystic fibrosis (CF)
Visit the Hogan Lab.
Waddell A, Ahrens R, Tsai YT, Sherrill JD, Denson LA, Steinbrecher KA, Hogan SP. Intestinal CCL11 and eosinophilic inflammation is regulated by myeloid cell-specific RelA/p65 in mice. J Immunol. 2013 May 1;190(9):4773-85.
Ahrens R, Osterfeld H, Wu D, Arumugam M, Groschwitz K, Strait RA, Finkelman FD, Hogan SP. Intestinal mast cell levels influence severity of oral antigen-induced anaphylaxis. Am J Pathol. 2012 Apr;180(4):1535-46.
Beichler A, Ahrens R, Steinbrecher K, Rothenberg ME, Munitz A, Denson L, Hogan SP. Colonic eosinophilic inflammation in experimental colitis is mediated by Ly6C+ CCR2+ inflammatory monocyte-derived CCL11. J Immunol. 2011 May 15;186(10):5993-6003.
Arumugam M, Ahrens R, Osterfeld H, Kottyan LC, Shang X, Maclennan JA, Zimmermann N, Zheng Y, Finkelman FD, Hogan SP. Increased susceptibility of 129SvEvBrd mice to IgE-Mast cell mediated anaphylaxis. BMC Immunol. 2011 Feb 3;12:14.
Wu D, Ahrens R, Osterfeld H, Noah TK, Groschwitz K, Foster PS, Steinbrecher KA, Rothenberg ME, Shroyer NF, Matthaei KI, Finkelman FD, Hogan SP. Interleukin-13 (IL-13)/IL-13 receptor alpha1 (IL-13Ralpha1) signaling regulates intestinal epithelial cystic fibrosis transmembrane conductance regulator channel-dependent Cl- secretion. Journal of Biological Chemistry. 2011;286(15), 13357-13369.
Osterfeld H, Ahrens R, Strait R, Rothenberg ME, Finkelman FD, Renauld JC, Hogan SP. Divergent roles for the IL9/IL9R-pathway in systemic antigen- and oral antigen-induced anaphylaxis. J Allergy Clin Immunol. 2010;125: 469-476.
Munitz A, Cole ET, Waddell A, Groschwitz K, Ahrens R, Steinbrecher K, Willson T, Han X, Denson L, Rothenberg ME, Hogan SP. Paired immunoglobulin-like receptor B (PIR-B) negatively regulates macrophage activation in experimental colitis. Gastroenterology. 2010;139(2), 530-541.
Groschwitz K, Ahrens R, Osterfeld H, Gurish MF, Abrink M, Finkelman F, Pejler G, Hogan SP. Mast cells regulate homeostatic intestinal epithelial migration and barrier function by a chymase/Mcpt4-dependent mechanism. Proceedings of the National Academy of Sciences of the United States of America. 2009;106(52), 22381-22386.
Ahrens R, Waddell A, Seidu L, Blanchard, C, Carey R, Forbes E, Lampinen M, Willson T, Cohen E, Stringer K, Ballard E, Munitz A, Xu H, Lee N, Lee JJ, Rothenberg ME, Denson L, Hogan SP. Intestinal macrophage/epithelial cell-derived CCL11/eotaxin-1 mediates eosinophil recruitment and function in pediatric ulcerative colitis. The Journal of Immunology. 2008;181(10), 7390-7399.
Forbes EE, Groschwitz K, Abonia JP, Brandt EB, Cohen E, Blanchard C, Ahrens R, Seidu L, McKenzie A, Strait R, Finkelman FD, Foster PS, Matthaei KI, Rothenberg ME, Hogan SP. IL-9- and mast cell-mediated intestinal permeability predisposes to oral antigen hypersensitivity. The Journal of Experimental Medicine. 2008;205(4), 897-913.
MiR-375 regulation of CFTR expression and Cl- secretory function. Principal Investigator. Cystic Fibrosis Foundation. Jul 2012-Jun 2014.
Eosinophil:M2 Macrophage:CCL11 Axis in Experimental Colitis and Pediatric Corticosteroid Resistant UC. Principal Investigator. National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases (NIH/NIDDK). Apr 2012-Mar 2016.
Epithelial Genes in Allergic Inflammation. Project 2 – Collaborating Investigator. National Institutes of Health/National Institute of Allergy and Infectious Diseases (NIH/NIAIDS). Sep 2006-Aug 2016.
Margaret K. Hostetter, MD BK Rachford Professor and Chair, Department of Pediatrics
studies the pathogenesis of bloodstream infections caused by the yeast Candida albicans. Her work has highlighted the role of C. albicans in biofilms, activation of human T cells, and evasion of innate immune mechanisms. Her clinical research is focused on the medical evaluation of internationally adopted children.
BK Rachford Professor and Chair, Department of Pediatrics
Bacterial and fungal infections; medical evaluation of internationally adopted children
Edith Janssen, PhD
focuses on mechanistic analysis and translational exploitation of the processes in dendritic cells that balance pro- and anti-inflammatory immune responses to self after cell death. Dr. Janssen aims at harnessing dendritic cells to develop effective autologous cancer vaccines. Her recent discovery (with Dr. Jonathan Katz) that dysregulation of such cells suggests a potential role for therapeutic modulation of these cells in autoimmune disease.
Hennies CM, Reboulet RA, Garcia Z, Nierkens S, Wolkers MC, Janssen EM. Selective expansion of merocytic dendritic cells and CD8DCs confers anti-tumour effect of Fms-like tyrosine kinase 3-ligand treatment in vivo. Clin Exp Immunol. 2011 Jan 14.
Reboulet RA, Hennies CM, Garcia Z, Nierkens S, Janssen EM. Prolonged antigen storage endows merocytic dendritic cells with enhanced capacity to prime anti-tumor responses in tumor-bearing mice. J Immunol. 2010 Sep 15;185(6):3337-47.
Katz JD, Ondr JK, Opoka RJ, Garcia Z, Janssen EM. Cutting edge: merocytic dendritic cells break T cell tolerance to beta cell antigens in nonobese diabetic mouse diabetes. J Immunol. 2010 Aug 15;185(4):1999-2003.
Janssen EM, Lemmens EE, Gour N, Reboulet RA, Green DR, Schoenberger SP, Pinkoski MJ. Distinct roles of cytolytic effector molecules for antigen-restricted killing by CTL in vivo. Immunol Cell Biol. 2010 Oct;88(7):761-5.
Krebs P, Barnes MJ, Lampe K, Whitley K, Bahjat KS, Beutler B, Janssen E, Hoebe K. NK-cell-mediated killing of target cells triggers robust antigen-specific T-cell-mediated and humoral responses. Blood. 2009 Jun 25;113(26):6593-602.
Kim-Saijo M, Janssen EM, Sugie K. CD4 cell-secreted, posttranslationally modified cytokine GIF suppresses Th2 responses by inhibiting the initiation of IL-4 production. Proc Natl Acad Sci U S A. 2008 Dec 9;105(49):19402-7.
Hildeman D, Janssen E. IFN-gamma and self-absorbed CD4+ T cells: a regulatory double negative. Nat Immunol. 2008 Nov;9(11):1210-2.
Benedict CA, Loewendorf A, Garcia Z, Blazar BR, Janssen EM. Dendritic cell programming by cytomegalovirus stunts naïve T cell responses via the PD-L1/PD-1 pathway. J Immunol. 2008 180:4836-4847.
Mothé B, Stewart B, Oseroff C, Bui H, Stogiera S, Garcia Z, Dow C, Rodriguez-Carreno M, Kotturi M, Pasquetto V, Botten J, Crotty S, Janssen E, Buchmeier M, Sette A . Chronic LCMV infection actively down regulates CD4+ T-cell responses directed against a broad range of epitopes. J Immunol. 2007 179:1058-1067.
Benedict CA, Janssen EM. Immunosuppression, learning from the masters. ERCI. 2007 3:659-662P.
Michael B. Jordan, MD
Histiocytic disorders: HLH and LCH
Better understanding histiocytic disorders and developing novel therapies for them; regulation of the immune response; immunotherapy of cancer
Marsh RA, Vaughn G, Kim MO, Li D, Jodele S, Joshi S, Mehta PA, Davies SM, Jordan MB, Bleesing JJ, Filipovich AH. Reduced-intensity conditioning significantly improves survival of patients with hemophagocytic lymphohistiocytosis undergoing allogeneic hematopoietic cell transplantation. Blood. 2010 Dec 23;116(26):5824-31.
Mehta PA, Vinks AA, Filipovich A, Bleesing J, Jodele S, Jordan MB, Marsh R, Tarin R, Edwards S, Fearing D, Lawrence J, Davies SM. Alternate-day micafungin antifungal prophylaxis in pediatric patients undergoing hematopoietic stem cell transplantation: a pharmacokinetic study. Biol Blood Marrow Transplant. 2010 Oct;16(10):1458-62.
Marsh RA, Madden L, Kitchen BJ, Mody R, McClimon B, Jordan MB, Bleesing JJ, Zhang K, Filipovich AH. XIAP deficiency: a unique primary immunodeficiency best classified as X-linked familial hemophagocytic lymphohistiocytosis and not as X-linked lymphoproliferative disease. Blood. 2010 Aug 19;116(7):1079-82.
Marsh RA, Satake N, Biroschak J, Jacobs T, Johnson J, Jordan MB, Bleesing JJ, Filipovich AH, Zhang K. STX11 mutations and clinical phenotypes of familial hemophagocytic lymphohistiocytosis in North America. Pediatr Blood Cancer. 2010 Jul 15;55(1):134-40.
Lin AA, Tripathi PK, Sholl A, Jordan MB, Hildeman DA. Gamma interferon signaling in macrophage lineage cells regulates central nervous system inflammation and chemokine production. J Virol. 2009 Sep;83(17):8604-15.
Marsh RA, Villanueva J, Kim MO, Zhang K, Marmer D, Risma KA, Jordan MB, Bleesing JJ, Filipovich AH. Patients with X-linked lymphoproliferative disease due to BIRC4 mutation have normal invariant natural killer T-cell populations. Clin Immunol. 2009 Jul;132(1):116-23.
Marsh RA, Villanueva J, Zhang K, Snow AL, Su HC, Madden L, Mody R, Kitchen B, Marmer D, Jordan MB, Risma KA, Filipovich AH, Bleesing JJ. A rapid flow cytometric screening test for X-linked lymphoproliferative disease due to XIAP deficiency. Cytometry B Clin Cytom. 2009 Sep;76(5):334-44.
Jordan MB, Filipovich AH. Hematopoietic cell transplantation for hemophagocytic lymphohistiocytosis: a journey of a thousand miles begins with a single (big) step. Bone Marrow Transplant. 2008 Oct;42(7):433-7.
Wojciechowski S, Jordan MB, Zhu Y, White J, Zajac AJ, Hildeman DA. Bim mediates apoptosis of CD127(lo) effector T cells and limits T cell memory. Eur J Immunol. 2006 Jul;36(7):1694-706.
Theodosia A. Kalfa, MD, PhD
Signaling in erythrocytes; erythropoiesis; sickle cell disease; reactive oxygen species
Visit the Kalfa Lab.
George A, Pushkaran S, Konstantinidis DG, Koochaki S, Malik P, Mohandas N, Zheng Y, Joiner CH, Kalfa TA. Erythrocyte NADPH oxidase activity modulated by Rac GTPases, PKC, and plasma cytokines contributes to oxidative stress in sickle cell disease. Blood. Epub ahead of print. 2013.
Konstantinidis DG, Pushkaran S, Johnson JF, Cancelas JA, Manganaris S, Harris CE, Williams DA, Zheng Y, Kalfa TA. Signaling and cytoskeletal requirements in erythroblast enucleation. Blood. 2012 Jun 21;119(25):6118-27.
Hammill AM, Risinger MA, Joiner CH, Keddache M, Kalfa TA. Compound heterozygosity for two novel mutations in the erythrocyte protein 4.2 gene causing spherocytosis in a Caucasian patient. Br J Haematol. 2011 Jan 31.
Kalfa TA. Anchoring at an island to relieve stress. Blood. 2011 Jan 20;117(3):748-9.
Mizukawa B, George A, Pushkaran S, Weckbach L, Kalinyak K, Heubi JE, Kalfa TA. Cooperating G6PD mutations associated with severe neonatal hyperbilirubinemia and cholestasis. Pediatr Blood Cancer. 2010 Oct 14.
Konstantinidis DG, George A, Kalfa TA. Rac GTPases in erythroid biology. Transfus Clin Biol. 2010 Sep;17(3):126-30.
Kalfa TA, Pushkaran S, Zhang X, Johnson JF, Pan D, Daria D, Geiger H, Cancelas JA, Williams DA, Zheng Y. Rac1 and Rac2 GTPases are necessary for early erythropoietic expansion in the bone marrow but not in the spleen. Haematologica. 2010 Jan;95(1):27-35.
Mulloy JC, Cancelas JA, Filippi MD, Kalfa TA, Guo F, Zheng Y. Rho GTPases in hematopoiesis and hemopathies. Blood. 2010 Feb 4;115(5):936-47.
Wang D, Zhang W, Kalfa TA, Grabowski G, Davies S, Malik P, Pan D. Reprogramming erythroid cells for lysosomal enzyme production leads to visceral and CNS cross-correction in mice with Hurler syndrome. Proc Natl Acad Sci U S A. 2009 Nov 24;106(47):19958-63.
Daria D, Filippi MD, Knudsen ES, Faccio R, Li Z, Kalfa T, Geiger H. The retinoblastoma tumor suppressor is a critical intrinsic regulator for hematopoietic stem and progenitor cells under stress. Blood. 2008 Feb 15;111(4):1894-902.
Rho GTPases in Terminal Erythroid Maturation. Principal Investigator. NIH/NHLBI. Sep 2012-Jun 2016. #1R01HL116352.
Erythrocyte Cytoskeleton Disorders Diagnostic Core. Principal Investigator. CCTST PCS T1 Pilot. July 2013- June 2015.
Cincinnati Center of Excellence in Hemoglobinopathies Research. Co-investigator. NIH/NHLBI. Aug 2013–May 2018. # U01 HL117709.
TCD with Transfusions Changing to Hydroxyurea. Co-investigator. NIH/Baylor. Aug 2009-Jul 2014. #R01HL095647.
Jonathan D. Katz, PhD
is working to understand the role that autoreactive T lymphocytes play in the Immunopathogenesis of type 1 diabetes, the most common pediatric autoimmune disease. Major focuses include defining: (a) the control of autoreactive T cells via central and peripheral tolerance; (b) the role NKT cells play in regulating autoreactive T cells; and (c) the role dendritic cells play in activating and regulating autoreactive T cells in type 1 diabetes.
T cells; MHC, beta cell death; islet antigens
Immunology, autoimmunity, type 1 diabetes
Jonathan D. Katz, PhD, focuses on autoimmune diabetes research. Autoimmune diabetes, also known as type 1 diabetes (T1D), is the most common pediatric autoimmune disease. Roughly 1/250 individuals develop T1D in the United States.There is currently no cure for T1D and the only treatment is daily exogenous insulin replacement therapy. Many T1D patients eventually develop secondary complications, such as hearth disease, blindness, peripheral neuropathy and renal failure.
Dr. Katz's work focuses on the role that autoreactive T lymphocytes play in the disease process. His lab interested in (1) the control of autoreactive T cells via central and peripheral tolerance, (2) the role NKT cells play in regulating autoreactive T cells, and (3) the role dendritic cells play in activating and regulating autoreactive T cells in T1D.
Most of his work uses the non-obese diabetic (NOD) mouse strain that spontaneously develops T1D with remarkable similar to the T1D seen in human patients. The availability of the NOD strain has allowed us to take a modern, reductionist molecular and cellular immunology approach to understanding the mechanism(s) and genetics underlying T1D susceptibility and disease progression. His lab makes extensive use of knockout, transgenic, regulated gene expression, targeted ablation, cell transfer and genomic studies the progression and regulation of T1D in the NOD mouse.
Katz JD, Ondr JK, Opoka RJ, Garcia Z, Janssen EM. Cutting edge: merocytic dendritic cells break T cell tolerance to beta cell antigens in nonobese diabetic mouse diabetes. J Immunol. 2010 Aug 15;185(4):1999-2003.
Pang S, Zhang L, Wang H, Yi Z, Li L, Gao L, Zhao J, Tisch R, Katz JD, Wang B. CD8(+) T cells specific for beta cells encounter their cognate antigens in the islets of NOD mice. Eur J Immunol. 2009 Oct;39(10):2716-24.
Saxena V, Ondr JK, Magnusen AF, Munn DH, Katz JD. The countervailing actions of myeloid and plasmacytoid dendritic cells control autoimmune diabetes in the nonobese diabetic mouse. J Immunol. 2007 Oct 15;179(8):5041-53.
Wojciechowski S, Tripathi P, Bourdeau T, Acero L, Grimes HL, Katz JD, Finkelman FD, Hildeman DA. Bim/Bcl-2 balance is critical for maintaining naive and memory T cell homeostasis. J Exp Med. 2007 Jul 9;204(7):1665-75.
Cain JA, Smith JA, Ondr JK, Wang B, Katz JD. NKT cells and IFN-gamma establish the regulatory environment for the control of diabetogenic T cells in the nonobese diabetic mouse. J Immunol. 2006 Feb 1;176(3):1645-54.
Vukkadapu SS, Belli JM, Ishii K, Jegga AG, Hutton JJ, Aronow BJ, Katz JD. Dynamic interaction between T cell-mediated beta-cell damage and beta-cell repair in the run up to autoimmune diabetes of the NOD mouse. Physiol Genomics. 2005 Apr 14;21(2):201-11.
Hutton JJ, Jegga AG, Kong S, Gupta A, Ebert C, Williams S, Katz JD, Aronow BJ. Microarray and comparative genomics-based identification of genes and gene regulatory regions of the mouse immune system. BMC Genomics. 2004 Oct 25;5(1):82.
Ashish R. Kumar, MD, PhD
Childhood cancer and blood disorders; immune deficiency
Leukemia biology; cancer biology
Visit the Kumar Lab.
Dr. Kumar received his medical degree from L.T.M. Medical College, Mumbai, India, his PhD in anatomy and cell biology from the University of Iowa, pediatric residency training at the Mayo Clinic and fellowship in pediatric hematology / oncology / BMT at the University of Minnesota. He was appointed to the faculty of the University of Minnesota in the Department of Pediatrics where he was a member of the programs in pediatric leukemia and global pediatrics. As a faculty of the Masonic Cancer Center, he was also part of the Genetic Mechanisms of Cancer research program. Dr. Kumar’s laboratory is engaged in researching the biology of infant leukemia. Discoveries made in his laboratory have significantly enhanced the current understanding of leukemia.
Kumar AR, Yao Q, Li Q, Sam TA, Kersey JH. t(4;11) leukemias display addiction to MLL-AF4 but not to AF4-MLL. Leuk Res. 2011 Mar;35(3):305-9.
Kumar AR, Sarver AL, Wu B, Kersey JH. Meis1 maintains stemness signature in MLL-AF9 leukemia. Blood. 2010 Apr 29;115(17):3642-3.
Burke MJ, Cao Q, Trotz B, Weigel B, Kumar A, Smith A, Verneris MR. Allogeneic hematopoietic cell transplantation (allogeneic HCT) for treatment of pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL). Pediatr Blood Cancer. 2009 Dec 15;53(7):1289-94.Kumar AR, Li Q, Hudson WA, Chen W, Yao Q, Sam TN, Wu B, Lund EA, Kowal BJ and Kersey JH. A role for MEIS1 in MLL-fusion gene leukemia. Blood. 2009 Feb 19; 113(8):1756-8. Chen W*, Kumar AR*, Hudson WA, Li Q, Wu B, Staggs RA, Lund EA, Sam TN and Kersey JH. Malignant transformation initiated by Mll-AF9: Gene dosage and critical target cells. Cancer Cell. 2008 May; 13: 432-440. *Co-first authors. Kris Ann P. Schultz, MD, Joseph P. Neglia, MD, MPH, Angela R. Smith, MD, Hans D. Ochs, MD, Dr. med., Troy R. Torgerson, MD, PhD, and Ashish Kumar, MD, PhD. Familial Hemophagocytic Lymphohistiocytosis in Two Brothers With X-Linked Agammaglobulinemia. Pediatric Blood and Cancer 2008; 51:293–295. White JG, Kumar AR, Hogan MJ. Gray Platelet Syndrome in a Somalian Family. Platelets. 2006 Dec; 17:519-527. Mehta PA, Davies SM, Kumar A, Devidas M, Lee S, Zamzow T, Elliott J, Villanueva J, Pullen J, Zewge Y, and Filipovich A; Children’s Oncology Group. Perforin polymorphism A91V and susceptibility to B-precursor childhood acute lymphoblastic leukemia: a report from the Children's Oncology Group. Leukemia. 2006 Sep; 20; 1539-1541. Chen W, Li Q, Hudson WA, Kumar A, Kirchhof N, Kersey JH. A murine Mll-AF4 knock-in model results in lymphoid and myeloid deregulation and hematological malignancy. Blood. 2006 Jul 15; 108:669-677.
Ian P. Lewkowich, PhD
investigates the factors that drive the development of severe allergic asthma, with a particular focus on the molecular mechanisms through which Th17 cytokines enhance IL-13 signaling, the regulation of the asthmatic response through the PD-1/PD-L axis and the mechanisms of the well-described maternal influence in inherited asthma risk.
While Th2 immune responses are central to disease pathology in allergic asthma, there is a growing understanding that the Th2 paradigm is not sufficient to explain the entire spectrum of disease severity. Indeed, there is growing belief that severe disease may be driven by a different process than mild to moderate disease.
Using a mouse model of allergic asthma in which one strain develops a phenotype characteristic of mild asthma (C3H/HeJ), and others develop a phenotype characteristic of severe disease (A/J), we have identified several novel mechanisms through which asthma severity is regulated. We have found that the development of severe allergic asthma is associated with a limited capacity of Tregs to limit pulmonary dendritic cell activity, enhanced capacity for antigen uptake by pulmonary myeloid dendritic cells, and the development of a mixed Th2/Th17 immune response. In contrast, C3H mice demonstrate increased Treg activity, preferential antigen uptake by pulmonary plasmacytoid dendritic cells, and an exclusively Th2-biased immune response. We are presently using the A/J versus C3H/HeJ mouse model of allergic asthma to tease out the mechanisms responsible the development of severe allergic asthma.
Lewkowich IP, Fox JG Perkins C, Lewis L, Finkelman FD Smith DE, Bryce PJ, Kurt-Jones EA, Wang TC, Sivaprasad U, Hershey GK, Herbert DR. Trefoil factor 2 rapidly induces interleukin 33 to promote type 2 immunity during allergic asthma and hookworm infection. J Exp Med. 2012;209(3):607-22.
Lufti R, Ledford JR, Zhou P, Lewkowich IP, Page K. Dendritic Cell-Derived Tumor Necrosis Factor α Modifies Airway Epithelial Cell Responses. J Innate Immun. 2012;4(5-6):542-52.
Lewkowich IP, Lajoie S, Stoffers SL, Suzuki Y, Richgels PK, Dienger K, Sproles AA, Yagita H, Hamid Q, Wills-Karp M. PD-L2 modulates asthma severity by directly decreasing dendritic cell IL-12 production. Mucosal Immunol. 2012.
Stefater JA, Lewkowich IP, Rao S, Ajima R, Mariggi G, Wills-Karp M, Pollard J, Yamaguchi T, McMahon AP, Ferrara N, Gerhardt H, Lang RA. Microglial Wnt ligands suppress retinal angiogenesis via activation of the VEGF inhibitor Flt1. Nature. 2011;474(7352):511-515.
Lewkowich IP, Day SB, Ledford JR, Zhou P, Dienger K, Wills-Karp M, Page K. Protease-activated receptor 2 activation of myeloid dendritic cells regulates allergic airway inflammation. Respir Res. 2011;(12):122.
Lewkowich IP1, Lajoie S1, Suzuki Y, Clark JR, Sproles AA, Dienger K, Budelsky A, and Wills-Karp M, Complement-mediated regulation of the IL-17A axis is a central genetic determinant of the severity of experimental allergic asthma. Nat Immunol. 2010;(10):928-935.
Chen G, Wan H, Luo F, Zhang L, Xu Y, Lewkowich IP, Wills-Karp M and Whitsett JA. Foxa2 programs Th2 cell-mediated innate immunity in the developing lung. J Immunol. 2010;(184):6133-6141.
Lewkowich IP, Lajoie S, Dienger K, Herman NS, Sproles AA, and Wills-Karp M. Enhanced allergen uptake, activation, and IL-23 production by pulmonary myeloid DCs drives airway hyperresponsiveness in asthma-susceptible mice. PLoS ONE. 2008;(3):e3879.
Köhl J, Baelder R, Lewkowich IP, Pandey MK, Hawlisch H, Wang L, Best J, Herman NS, Sproles AA, Zwirner J, Whitsett JA, Gerard C, Sfyroera G, Lambris JD, and Wills-Karp M. A regulatory role for the C5a anaphylotoxin on type 2 immunity in asthma. J Clin Invest. 2006;(116):783-796.
Lewkowich IP, Herman NS, Schleifer KW, Dance MP, Chen BL, Dienger KM, Sproles AA, Shah JS, Köhl J, Belkaid Y, and Wills-Karp M. CD4+CD25+ T cells protect against experimentally induced asthma and alter pulmonary dendritic cell phenotype and function. J Exp Med. 2005;(202):1549-1561.
Punam Malik, MD Marjory J. Johnson Chair of Gene and Cell Therapy
works to correct the gene responsible for sickle cell anemia. One of our lab’s major projects uses gene therapy to treat sickle cell disease. His lab is also interested in gene therapy for other diseases. He has developed various methods for delivering corrective genes to cells, improving methods for gene therapy in general.
Marjory J. Johnson Chair of Gene and Cell Therapy
Director, Comprehensive Sickle Cell Program
Director, Translational Trials Development and Support Laboratory
Program Leader, Hematology and Gene Therapy Program
Arumugam P, Malik P. Genetic therapy for beta-thalassemia: from the bench to the bedside. Hematology Am Soc Hematol Educ Program. 2010;2010:445-50.
Perumbeti A, Malik P. Therapy for beta-globinopathies: a brief review and determinants for successful and safe correction. Ann N Y Acad Sci. 2010 Aug;1202:36-44. Review.
Perumbeti A, Malik P. Genetic correction of sickle cell anemia and beta-thalassemia: progress and new perspective. Scientific World Journal. 2010 Apr 13;10:644-54. Review.
Sundaram N, Tailor A, Mendelsohn L, Wansapura J, Wang X, Higashimoto T, Pauciulo MW, Gottliebson W, Kalra VK, Nichols WC, Kato GJ, Malik P. High levels of placenta growth factor in sickle cell disease promote pulmonary hypertension. Blood. 2010 Jul 8;116(1):109-12.
Arumugam PI, Urbinati F, Velu CS, Higashimoto T, Grimes HL, Malik P. The 3' region of the chicken hypersensitive site-4 insulator has properties similar to its core and is required for full insulator activity. PLoS One. 2009 Sep 10;4(9):e6995.
Arumugam PI, Higashimoto T, Urbinati F, Modlich U, Nestheide S, Xia P, Fox C, Corsinotti A, Baum C, Malik P. Genotoxic potential of lineage-specific lentivirus vectors carrying the beta-globin locus control region. Mol Ther. 2009 Nov;17(11):1929-37.
Perumbeti A, Higashimoto T, Urbinati F, Franco R, Meiselman HJ, Witte D, Malik P. A novel human gamma-globin gene vector for genetic correction of sickle cell anemia in a humanized sickle mouse model: critical determinants for successful correction. Blood. 2009 Aug 6;114(6):1174-85.
Urbinati F, Arumugam P, Higashimoto T, Perumbeti A, Mitts K, Xia P, Malik P. Mechanism of reduction in titers from lentivirus vectors carrying large inserts in the 3'LTR. Mol Ther. 2009 Sep;17(9):1527-36.
Williams JP, Wu J, Johansson G, Rizvi TA, Miller SC, Geiger H, Malik P, Li W, Mukouyama YS, Cancelas JA, Ratner N. Nf1 mutation expands an EGFR-dependent peripheral nerve progenitor that confers neurofibroma tumorigenic potential. Cell Stem Cell. 2008 Dec 4;3(6):658-69.
Alexander G. Miethke, MD
is interested in susceptibility factors for neonatal liver injury, including biliary atresia. He focuses on the interaction between the maturing adaptive immune system and hepatic immune responses to infectious insults during the early neonatal period.
Pediatric liver disease including biliary atresia, inherited liver diseases, autoimmune hepatitis, and primary sclerosing cholangitis; gastrointestinal problems in children with bone marrow failure syndromes
Immune mediated liver injury, specifically the role of regulatory T cells in biliary atresia and primary sclerosing cholangitis; genetic basis for intrahepatic cholestasis in children; acute liver failure in infants with mitochondrial disorders
MD: Humboldt-University, Berlin, Germany, 2000.Residency: Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 2002-2004.Fellowship: Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 2005-2007.
Advanced Fellowship: Pediatric Transplant Hepatology, University of Cincinnati and Cincinnati Children's Hospital Medical Center, 2009.Certification: Pediatrics, 2005; Pediatric Gastroenterology 2009; Pediatric Transplant Hepatology, 2010.
Evason K, Bove KE, Finegold MJ, Knisely AS, Rhee S, Rosenthal P, Miethke AG, Karpen SJ, Ferrell LD, Kim GE. Morphologic findings in progressive familial intrahepatic cholestasis 2 (PFIC2): correlation with genetic and immunohistochemical studies. Am J Surg Pathol. 2011;35:687-96.
Miethke AG, Saxena V, Shivakumar P, Sabla GE, Simmons J, Chougnet CA. Post-natal paucity of regulatory T cells and control of NK cell activation in experimental biliary atresia. J Hepatol. 2010 May;52(5):718-26.
Liu C, Aronow BJ, Jegga AG, Wang N, Miethke A, Mourya R, Bezerra JA. Novel resequencing chip customized to diagnose mutations in patients with inherited syndromes of intrahepatic cholestasis. Gastroenterology. 2007 Jan;132(1):119-26.
Shivakumar P, Campbell KM, Sabla GE, Miethke A, Tiao G, McNeal MM, Ward RL, Bezerra JA. Obstruction of extrahepatic bile ducts by lymphocytes is regulated by IFN-gamma in experimental biliary atresia. J Clin Invest. 2004 Aug;114(3):322-9.
Sean R. Moore, MS, MD
is interested in the vicious cycle of childhood diarrhea and malnutrition in developing countries, with a current focus on the mechanisms of a promising glutamine-based oral rehydration and nutrition therapy. Dr. Moore studies the signaling pathways by which alanyl-glutamine promotes gut homeostasis and also collaborates with colleagues on the epidemiology and impact of early childhood diarrhea and undernutrition in impoverished settings.
General gastroenterology; inflammatory bowel diseases
Diarrheal diseases; glutamine; global health
Moore SR. Update on prolonged and persistent diarrhea in children. Curr Opin Gastroenterol. 2010 Sep 10.
Moore SR, Lima NL, Soares AM, Oriá RB, Pinkerton RC, Barrett LJ, Guerrant RL, Lima AA. Prolonged episodes of acute diarrhea reduce growth and increase risk of persistent diarrhea in children. Gastroenterology. 2010 Oct;139(4):1156-64.
Guerrant RL, Oriá RB, Moore SR, Oriá MOB, Lima AA. Malnutrition as an enteric infectious disease, with long-term effects on child development. Nutr Rev. 2008;66(9):487-505.Checkley W, Buckley G, Gilman RH, Assis AM, Guerrant RL, Morris SS, Mølbak K, Valentiner-Branth P, Lanata CF, Black RE. Multi-country analysis of the effects of diarrhoea on childhood stunting. Int J Epidemiol. 2008;37(4):816-30. Moore SR, Lorntz B, Lima AA, Guerrant RL. Risk factors for adverse outcomes in developing countries. Lancet. 2007;369(9564):824-5.
Ardythe L. Morrow, PhD Director, Center for Interdisciplinary Research in Human Milk & Lactation
Director, Center for Interdisciplinary Research in Human Milk & Lactation
Human milk; child health and nutrition
Dr. Morrow received her MSc in nutrition from the University of the West Indies, Kingston, Jamaica (1980) and PhD in epidemiology from the University of Texas at Houston (1991). Since 1987 she has worked with colleagues in Mexico, Boston, and Houston on an NIH-funded program project on human milk immune protection against infectious disease.
She is currently Professor of Pediatrics at the University of Cincinnati College of Medicine and Cincinnati Children's Hospital Medical Center, where she founded and directs the Center for Epidemiology and Biostatistics that has 35 faculty and staff and a multi-disciplinary Human Milk Research Program that includes clinical and basic science investigators in eight divisions.
She has published extensively on breastfeeding promotion and human milk protection against infectious diseases. Her primary focus is on protection by human milk glycans and protection against infectious disease, but she has expanded her research to understanding the relationship between breastfeeding and chronic diseases. She has been an ad hoc reviewer for NIH on breastfeeding research and a technical advisor for international breastfeeding policy and programs for Gates Foundation, UNICEF, and WHO, is on the editorial board of the Journal of Human Lactation and the journal of the Academy of Breastfeeding Medicine. She is an elected member of the American Pediatric Society. She has over 100 publications, and is the primary author of the WHO monograph, Community-based Strategies for Breastfeeding Promotion and Support in Developing Countries (2004).
She has served as Chair of the Milk Club of the (American) Society for Pediatric Research for the past 4 years. In 1997, she received a Young Investigator award from ISRHML for her randomized trial of breastfeeding support (Lancet, 1999). She was co-organizer of the 2002 ISRHML international meeting in Mexico and is co-editor of the book Protecting Infants through Human Milk: Advancing the Scientific Evidence.
South AP, Wessel JJ, Sberna A, Patel M, Morrow AL. Hospital readmission among infants with gastroschisis. J Perinatol. 2011 Feb 10.
Morrow AL, Meinzen-Derr J, Huang P, Schibler KR, Cahill T, Keddache M, Kallapur SG, Newburg DS, Tabangin M, Warner BB, Jiang X. Fucosyltransferase 2 Non-Secretor and Low Secretor Status Predicts Severe Outcomes in Premature Infants. J Pediatr. 2011 May;158(5):745-51.
Farkas T, Cross RW, Hargitt E 3rd, Lerche NW, Morrow AL, Sestak K. Genetic diversity and histo-blood group antigen interactions of rhesus enteric caliciviruses. J Virol. 2010 Sep;84(17):8617-25.
Woo JG, Guerrero ML, Altaye M, Ruiz-Palacios GM, Martin LJ, Dubert-Ferrandon A, Newburg DS, Morrow AL. Human milk adiponectin is associated with infant growth in two independent cohorts. Breastfeed Med. 2009 Jun;4(2):101-9.
Huang P, Morrow AL, Jiang X. The carbohydrate moiety and high molecular weight carrier of histo-blood group antigens are both required for norovirus-receptor recognition. Glycoconj J. 2009 Nov;26(8):1085-96.
Meinzen-Derr J, Morrow AL, Hornung RW, Donovan EF, Dietrich KN, Succop PA. Epidemiology of necrotizing enterocolitis temporal clustering in two neonatology practices. J Pediatr. 2009 May;154(5):656-61.
Geraghty SR, Khoury JC, Morrow AL, Lanphear BP. Reporting individual test results of environmental chemicals in breast milk: potential for premature weaning. Breastfeed Med. 2008 Dec;3(4):207-13.
Olsen IE, Lawson ML, Meinzen-Derr J, Sapsford AL, Schibler KR, Donovan EF, Morrow AL. Use of a body proportionality index for growth assessment of preterm infants. J Pediatr. 2009 Apr;154(4):486-91.
Meinzen-Derr J, Poindexter B, Wrage L, Morrow AL, Stoll B, Donovan EF. Role of human milk in extremely low birth weight infants' risk of necrotizing enterocolitis or death. J Perinatol. 2009 Jan;29(1):57-62.
Woo JG, Dolan LM, Morrow AL, Geraghty SR, Goodman E. Breastfeeding helps explain racial and socioeconomic status disparities in adolescent adiposity. Pediatrics. 2008 Mar;121(3):e458-65.
Takahisa Nakamura, PhD
RNA-related inflammation in obesity and metabolic diseases
Dr. Nakamura received his PhD from the University of Tokyo in 2003. He completed postdoctoral training in the laboratory of Dr. Gökhan S. Hotamisligil at Harvard School of Public Health in 2013, followed by his faculty appointment at Cincinnati Children's Hospital in 2013.
PhD: University of Tokyo, 2003.
Postdoctoral Fellow: University of Tokyo, 2003-2006
Research Fellow: Harvard University, 2006-2010
Research Associate: Harvard University, 2010-2013
Takahisa Nakamura, Alessandro Arduini, Brenna Baccaro, Masato Furuhashi, and Gökhan S. Hotamisligil. Small molecule inhibitors of PKR improve glucose homeostasis in obese, diabetic mice. Diabetes. 2013 In press
Lu B, Nakamura T, Inouye K, Li J, Tang Y, Lundbäck P, Valdes-Ferrer SI, Olofsson PS, Kalb T, Roth J, Zou Y, Erlandsson-Harris H, Yang H, Ting JP, Wang H, Andersson U, Antoine DJ, Chavan SS, Hotamisligil GS, Tracey KJ. Novel role of PKR in inflammasome activation and HMGB1 release. Nature. 2012 Aug 20;488(7413):670-4. Morita M. Oike Y, Nagashima T, Kadomatsu T, Tabata M, Suzuki T, Nakamura T, Yoshida N, Okada M, Yamamoto T. Obesity resistance and increased hepatic expression of catabolism-related mRNAs in Cnot3(+/-) mice. EMBO J. 2011 Sep 6;30(22):4678-4691. Nakamura T, Furuhashi M, Li P, Cao H, Tuncman G, Sonenberg N, Gorgun CZ, Hotamisligil GS. Double-stranded RNA-dependent Protein Kinase Links Pathogen Sensing with Stress and Metabolic Homeostasis. Cell. 2010 Feb 5;140(3):338-48. Yoneda M, Suzuki T, Nakamura T, Ajima R, Yoshida Y, Kakuta S, Sudo K, Iwakura Y, Shibutani M, Mitsumori K, Yokota J, Yamamoto T. Deficiency of antiproliferative family protein Ana correlates with development of lung adenocarcinoma. Cancer Sci. 2009 Feb;100(2):224-232. Ajima R, Akiyama T, Usui M, Yoneda M, Yoshida Y, Nakamura T, Minowa O, Noda M, Tanaka S, Noda T, Yamamoto T. Osteoporotic bone formation in mice lacking tob2; involvement of Tob2 in RANK ligand expression and osteoclasts differentiation. FEBS Lett. 2008 Apr 16;582(9):1313-8. Morita M, Suzuki T, Nakamura T, Yokoyama K, Miyasaka T, Yamamoto T. Depletion of mammalian CCR4b deadenylase triggers elevation of the p27Kip1 mRNA level and impairs cell growth. Mol Cell Biol. 2007 Jul;27(13):4980-90. Nakamura T, Yao R, Ogawa T, Suzuki T, Ito C, Tsunekawa N, Inoue K, Ajima R, Miyasaka T, Yoshida Y, Ogura A, Toshimori K, Noce T, Yamamoto T, Noda T. Oligoasthenoteratozoospermia in mice lacking Cnot7, a regulator of retinoid X receptor beta. Nat Genet. 2004 May;36(5):528-33.Kimura H*, Nakamura T*, Ogawa T, Tanaka S, Shiota K. Transcription of mouse DNA methyltransferase 1 (Dnmt1) is regulated by both E2F-Rb-HDAC-dependent and -independent pathways. Nucleic Acids Res. 2003 Jun 15;31(12):3101-13. *These authors contributed equally to this work. Yoshida Y*, Nakamura T*, Komoda M, Satoh H, Suzuki T, Tsuzuku JK, Miyasaka T, Yoshida EH, Umemori H, Kunisaki RK, Tani K, Ishii S, Mori S, Suganuma M, Noda T, Yamamoto T. Mice lacking a transcriptional corepressor Tob are predisposed to cancer. Genes Dev. 2003 May 15;17(10):1201-6. *These authors contributed equally to this work.
Joseph E. Qualls, PhD
examines the cellular and molecular facets of macrophage biology during health and disease. This white blood cell has an unprecedented role in regulating inflammation, pathogen elimination and maintaining tissue homeostasis. Specifically, Dr. Qualls’ laboratory focuses on amino acid utilization by macrophages, and how this affects the outcome of infection and inflammatory disease.
Immunology; innate immunity; macrophage biology; amino acid metabolism; intracellular pathogenesis
Dr. Qualls completed his undergraduate work in 2002, receiving his BA summa cum laude in biology from Thomas More College in Crestview Hills, Kentucky. He then joined the laboratory of Don Cohen, PhD, in the Department of Microbiology, Immunology and Molecular Genetics at the University of Kentucky, where he studied the role of macrophages and dendritic cells during the development of inflammatory bowel disease. After defending his thesis and receiving his PhD in 2007, Dr. Qualls began his postdoctoral training with Peter Murray, PhD, in the Department of Infectious Diseases and Immunology at St. Jude Children’s Research Hospital in Memphis, Tennessee, where his research helped to define the functional plasticity of macrophages in response to infection and cancer. During his postdoctoral training, Dr. Qualls received a Ruth L. Kirschstein National Research Service Award and actively participated as vice chair of Mentoring Activities within the Postdoctoral Association Council and as a member of the Education Programs Committee.
Dr. Qualls’ long-term goals are to understand the interplay between nutrition, metabolism and immune regulation during anti-pathogen defense. He has focused on how macrophages use the amino acid, L-arginine, to combat intracellular pathogens. As a starting point to appreciate broader principles of immunity and metabolism he established a map of L-arginine metabolism at the transcriptomic and metabolomic levels. His laboratory now uses this map to dissect how L-arginine generates anti-microbial effectors, how this pathway is regulated, and how microbes can hijack the pathway. His current research has two complementary tracks that retain initial focus on L-arginine metabolism in macrophages, but will eventually broaden into larger issues concerning metabolism in immunity.
Current research: Many groups have shown that T cell function is inhibited via byproducts of L-arginine metabolism or when extracellular L-arginine becomes limiting. In one project, the laboratory is focused on characterizing the in vivo function of L-arginine utilization by macrophages during mycobacterial infection, and how this affects anti-pathogen T cell function. In parallel, the laboratory is addressing the provocative role of L-arginine biosynthesis from L-citrulline during intracellular infection, and how this mechanism is regulated at the cellular level. While greatly unexplored, this pathway of amino acid recycling is vital as mice deficient in L-arginine biosynthesis, compared to normal mice, lack efficient control of both M. bovis BCG and M. tuberculosis infection.
BA: Thomas More College, Crestview Hills, KY, 2002.
PhD: University of Kentucky, Lexington, KY, 2007.
Postdoctoral Fellowship: St. Jude Children’s Research Hospital, Memphis, TN, 2012.
Qualls JE, Subramanian C, Smith AM, Balouzian L, DeFreitas AA, Shirey KA, Reutterer B, Kernbauer E, Stockinger S, Decker T, Miyairi I, Vogel SN, Rock CO, Murray PJ. Sustained generation of nitric oxide and control of mycobacterial infection requires argininosuccinate synthase 1. Cell Host & Microbe. 2012 Sept 13;12(3):313-23.
Smith AM, Qualls JE, O’Brien K, Balouzian L, Johnson PF, Schultz-Cherry S, Smale ST, Murray PJ. A Distal Enhancer in Il12b is the Target of Transcriptional Repression by the Stat3 Pathway and Requires the B-Zip Protein NFIL-3. Journal of Biological Chemistry. 2011 Jul 1;286(26):23582-90.
Qualls JE, Murray PJ. Tumor Macrophages: Protective and Pathogenic Roles in Cancer Development. Current Topics in Developmental Biology. 2011;94:309-28.
Qualls JE, Neale G, Smith AM, Koo MS, DeFreitas AA, Zhang H, Kaplan G, Watowich SS, Murray PJ. Arginine usage in mycobacteria-infected macrophages depends on autocrine-paracrine cytokine signaling. Science Signaling. 2010 Aug 17;3(135):ra62.
Qualls JE, Murray PJ. A double agent in cancer: stopping macrophages wounds tumors. Nature Medicine. 2010 Aug;16(8):863-4.
Qualls JE, Tuna H, Kaplan AM, Cohen DA. Dendritic Cell-Mediated Suppression of Dextran Sodium Sulfate-Induced Colitis in Mice. Inflammatory Bowel Disease.
El Kasmi KC, Qualls JE (co-primary author), Pesce JT, Smith AM, Thompson RW, Henao-Tamayo M, Basaraba RJ, König T, Schleicher U, Koo M, Kaplan G, Fitzgerald KA, Tuomanen EI, Orne IM, Kanneganti T, Bogdan C, Wynn TA, and Murray PJ. TLR-induced Arginase 1 thwarts effective immunity against intracellular pathogens. Nature Immunology. 2008 Dec;9(12):1399-406.
Moreira LO, Smith AM, DeFreitas AA, Qualls JE, El Kasmi KC, Murray PJ. Modulation of adaptive immunity by different adjuvant-antigen combinations in mice lacking Nod2. Vaccine. 2008 Oct 29;26(46):5808-13.
Qualls JE, Kaplan AM, van Rooijen N, Cohen DA. Suppression of Experimental Colitis by Intestinal Mononuclear Phagocytes. Journal of Leukocyte Biology. 2006 Oct;80(4):802-15.
Burnett SH, Beus BJ, Avdiushko R, Qualls J, Kaplan AM, Cohen DA. Development of Peritoneal Adhesions in Macrophage Depleted Mice. Journal of Surgical Research. 2006 Apr;131(2):296-301.
Nancy Ratner, PhD Beatrice C. Lampkin Chair, Cancer Biology
is working to define the interactions between glial cells and axons during nervous system development and how those interactions go awry in disease. Her goal is to develop novel therapies for patients with nervous system diseases.
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Beatrice C. Lampkin Chair, Cancer Biology
Development of the nervous system; peripheral nerve tumor formation
Genetic mutations in tumor suppressor genes
Nancy Ratner, PhD, is interested in understanding mechanisms of peripheral nerve tumor (neurofibroma) formation in Neurofibromatosis type 1 (NF1), a common inherited disorder in which children are predisposed to cancer of the nervous system, to learning problems, bone disorders, and other cancers. She identified EGFR as a potential therapeutic target in NF1 peripheral nerve tumorigenesis, and has developed cell culture and mouse models of NF1 nerve tumorigenesis. Her laboratory has also used analysis of gene expression to identify critical genes in neurofibroma and their malignant derivatives, MPNST.
Dr. Ratner received her bachelor's from Brown University, her doctorate from Indiana University, and was a postdoctoral fellow at Washington University in St. Louis. She was a member of the faculty at the University of Cincinnati from 1987 to 2004. Dr. Ratner is currently a professor in the Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, and the program leader for Cancer Biology and Neural Tumors Program in the Cancer and Blood Diseases Institute where she holds the Beatrice C. Lampkin Endowed chair in cancer biology and serves as PI of the NINDS P50 “Cincinnati Center in NF Research”.
Dr. Ratner is an active member of the International Consortium on the Molecular Biology of NF1, NF2, and schwannomatosis and was a member of the advisory board for the National Neurofibromatosis Foundation (now Children’s Tumor Foundation) from 1989 to 2007. She chaired the Department of Defense Neurofibromatosis Research Program Integration Panel in 2008, and currently serves as a member of the James McDonnell Brain Tumor Research Advisory Board. She received the von Recklinghausen Award from the Children’s Tumor Foundation in 2010.
PhD: Indiana University, 1982.
BA: Brown University, 1975.
Fellowship: Washington University St. Louis, 1982-1987.
Mayes DA, Rizvi TA, Cancelas JA, Kolasinski NT, Ciraolo GM, Stemmer-Rachamimov AO, Ratner N. Perinatal or Adult Nf1 Inactivation Using Tamoxifen-Inducible PlpCre Each Cause Neurofibroma Formation. Cancer Res. 2011 Jul 1;71(13):4675-85.
Shang X, Cancelas JA, Li L, Guo F, Liu W, Johnson JF, Ficker A, Daria D, Geiger H, Ratner N, Zheng YR. Ras and Rac1 GTPase Crosstalk Regulates Hematopoietic Progenitor Cell Migration, Homing and Mobilization. Biol Chem. 2011 May 13.
Wu. J, Dombi E, Jousma E, Dunn SR, Lindquist D, Kim M, Kim A, Cripe TP, Ratner N. Preclinical testing of sorafenib and RAD001 in the Nf(flox/flox); DhhCre mouse model of plexiform neurofibroma using magnetic resonance imaging. Pediatr Blood Cancer. 2012 Feb;58(2):173-80.
Hummel TR, Jessen WJ, Miller SC, Kluwe L, Mautner VF, Wallace MR, Lázaro C, Page G, Worley P, Aronow BJ, Schorry E, Ratner N. Gene expression analysis identifies potential biomarkers of neurofibromatosis type 1 including adrenomedullin. Clin Cancer Res. 2010;16 5048-57.
Ryan MA, Nattamai KJ, Xing E, Schleimer D, Daria D, Sengupta A, Köhler A, Liu W, Gunzer M, Jansen M, Ratner N, Le Cras TD, Waterstrat A, Van Zant G, Cancelas JA, Zheng Y, Geiger H. Pharmacological inhibition of EGFR signaling enhances G-CSF induced hematopoietic stem cell mobilization. Nature Med. 2010 16(10):1141-6.
Miller SJ, Lan Z, Hardiman A, Wu J, Kordich JJ, Patmore D, Hegde R, Cripe TP, Cancelas J, Collins M, Ratner N. Inhibition of Eyes Absent Homolog 4 expression induces malignant peripheral nerve sheath tumor necrosis. Oncogene. 2009 29(3):368-79.
Miller SJ, Jessen WJ, Mehta T, Hardiman A, Sites E, Kaiser S, Jegga A, Li H, Upadhyaya M, Giovannini M, Muir D, Wallace MR, Lopez E, Serra E, Lazaro C, Stemmer-Rachamimov A, Page G, Aronow BJ, Ratner N. Integrative genomic analyses of neurofibromatosis tumors identify SOX9 as biomarker and survival gene. EMBO Mol. Medicine. 2009 1(4): 236-48.
Mahller Y, Williams J, Baird W, Mitton B, Grossheim J, Saeki Y, Cancelas J, Ratner N, Cripe T. Neuroblastoma cell lines contain pluripotent tumor initiating cells that are susceptible to a targeted oncolytic virus. PLoS ONE. 2009 4(1):e4235, 1– 0.
Williams JP, Wu J, Johansson G, Rizvi T, Miller SC, Geiger H, Malik P, Li W, Mukouyama Y, Cancelas JA, Ratner N. Nf1 mutation expands an EGFR-dependent peripheral nerve progenitor population that confers neurofibroma tumorigenic potential. Cell Stem Cell. 2008 3(6):658-69.
Johansson G, Mahller Y, Collins MH, Kim M-O, Nobukuni T, Perentesis JP, Cripe TP, Lane HA, Kozma S, Thomas G, Ratner N. Effective In Vivo Targeting of the mTOR Pathway in Malignant Peripheral Nerve Sheath Tumor. Mol. Cancer Therapeutics. 2008 7(5):1237-45.
Marc E. Rothenberg, MD, PhD Director, Division of Allergy and Immunology
is focused on elucidating mechanisms of allergic responses, especially in mucosal tissues such as the lung and the gastrointestinal tract, in order to identify novel pharmaceutical targets for treatment of patients with eosinophilic diseases including eosinophilic gastrointestinal disorders, hypereosinophilic syndromes and asthma and food allergies. Lab has identified and characterized several critical pathways that regulate allergic responses.
Visit the Rothenberg Lab web site
Director, Division of Allergy and Immunology
Director, Cincinnati Center for Eosinophilic Disorders
Eosinophilia; eosinophilic disorders; asthma; allergy; food allergy
Visit the Rothenberg Lab.
Dr. Rothenberg is director of the Division of Allergy/Immunology at Cincinnati Children's Hospital Medical Center and tenured professor of pediatrics at Cincinnati Children’s and University of Cincinnati College of Medicine. He graduated summa cum laude with highest honors in chemistry and biochemistry from Brandeis University. He then completed the MD/PhD program at Harvard Medical School under Dr. Frank Austen, conducting studies on eosinophil hematopoiesis, as he developed the first culture system for human eosinophils. After completing residency at Children’s Hospital, Boston, Dr. Rothenberg did a fellowship in allergy/immunology and hematology at Children’s Hospital. Dr. Rothenberg did post-doctorate training with Dr. Philip Leder, Harvard Medical School, where he cloned the eotaxin chemokine. After being faculty at Harvard Medical School for one year, he came to the University of Cincinnati and Cincinnati Children's, where he has helped build a top program in research, and his division is a leader in allergy and immunology.
His research is focused on molecular analysis of allergic inflammation, primarily on the molecular pathogenesis of eosinophilic esophagitis. His laboratory takes a multi-disciplinary approach including the development of preclinical murine models: genetics, genomics, molecular immunology, and biochemistry. Dr. Rothenberg’s awards include the 2007 E Mead Johnson Award from the Society of Pediatric Research, 2010 National Institutes of Health MERIT Award, and being elected an American Association for the Advancement of Science fellow. He is a member of the American Society for Clinical Investigation, American Academy of Pediatrics, and Society for Pediatric Radiology. His publications number over 300. He has served on review panels for journals/grant agencies including National Institutes of Health (NIH), Burroughs Trust, and Medical Research Council of the United Kingdom. He served for four-years on the Advisory Council of National Institute of Allergy and Infectious Disease. He has been associate editor of the Journal of Allergy and Clinical Immunology since 2004. His research has been supported by sources including the NIH, Human Frontier Science Program Organization, Burroughs Wellcome Fund, Dana Foundation, and Department of Defense.
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MD, PhD: Harvard Medical School, Cambridge, MA, 1990.
Residency: Pediatrics, Children's Hospital, Boston, MA, 1991-1992.
Fellowship: Immunology / Allergy, Children's Hospital, Boston, MA, 1992-1994; Hematology / Oncology, Children's Hospital and Dana Farber Cancer Institute, Boston, MA, 1992-1995.
Certification: National Board of Medical Examiners, 1991; Board of Registration in Medicine, MA, 1992; American Board of Pediatrics, 1995, 2001, 2008; Ohio State Medical Board, 1997; American Board of Allergy and Immunology, 1997, 2006.
Butz BK, Wen T, Gleich GJ, Furuta GT, Spergel J, King E, Kramer RE, Collins MH, Stucke E, Mangeot C, Jackson WD, O'Gorman M, Abonia JP, Pentiuk S, Putnam PE, Rothenberg ME. Efficacy, dose reduction, and resistance to high-dose fluticasone in patients with eosinophilic esophagitis. Gastroenterology. 2014; In press.
Sherrill JD, Kc K, Wu D, Djukic Z, Caldwell JM, Stucke EM, Kemme KA, Costello MS, Mingler MK, Blanchard C, Collins MH, Abonia JP, Putnam PE, Dellon ES, Orlando RC, Hogan SP, Rothenberg ME. Desmoglein-1 regulates esophageal epithelial barrier function and immune responses in eosinophilic esophagitis. Mucosal Immunol. 2014 May;7(3):718-29.
Wen T, Stucke EM, Grotjan TM, Kemme KA, Abonia JP, Putnam PE, Franciosi JP, Garza JM, Kaul A, King EC, Collins MH, Kushner JP, Rothenberg ME. Molecular diagnosis of eosinophilic esophagitis by gene expression profiling. Gastroenterology. 2013 Dec;145(6):1289-99.
Wen T, Besse JA, Mingler MK, Fulkerson PC, Rothenberg ME. Eosinophil adoptive transfer system to directly evaluate pulmonary eosinophil trafficking in vivo. Proc Natl Acad Sci U S A. 2013 Apr 9;110(15):6067-72
Lu TX, Sherrill JD, Wen T, Plassard AJ, Besse JA, Abonia JP, Franciosi JP, Putnam PE, Eby M, Martin LJ, Aronow BJ, Rothenberg ME. MicroRNA signature in patients with eosinophilic esophagitis, reversibility with glucocorticoids, and assessment as disease biomarkers. J Allergy Clin Immunol. 2012 Apr;129(4):1064-75.e9.
Rothenberg ME, Spergel JM, Sherrill JD, Annaiah K, Martin LJ, Cianferoni A, Gober L, Kim C, Glessner J, Frackelton E, Thomas K, Blanchard C, Liacouras C, Verma R, Aceves S, Collins MH, Brown-Whitehorn T, Putnam PE, Franciosi JP, Chiavacci RM, Grant SF, Abonia JP, Sleiman PM, Hakonarson H. Common variants at 5q22 associate with pediatric eosinophilic esophagitis. Nat Genet. 2010 Apr;42(4):289-91.
Rothenberg ME, Klion AD, Roufosse FE, Kahn JE, Weller PF, Simon HU, Schwartz LB, Rosenwasser LJ, Ring J, Griffin EF, Haig AE, Frewer PI, Parkin JM, Gleich GJ; Mepolizumab HEC Study Group. Treatment of patients with the hypereosinophilic syndrome with mepolizumab. N Engl J Med. 2008 Mar 20;358(12):1215-28.
Blanchard C, Wang N, Stringer KF, Mishra A, Fulkerson PC, Abonia JP, Jameson SC, Kirby C, Konikoff MR, Collins MH, Cohen MB, Akers R, Hogan SP, Assa'ad AH, Putnam PE, Aronow BJ, Rothenberg ME. Eotaxin-3 and a uniquely conserved gene-expression profile in eosinophilic esophagitis. J Clin Invest. 2006 Feb;116(2):536-47.
Hogan SP, Mishra A, Brandt EB, Royalty MP, Pope SM, Zimmermann N, Foster PS, Rothenberg ME. A pathological function for eotaxin and eosinophils in eosinophilic gastrointestinal inflammation. Nat Immunol. 2001 Apr;2(4):353-60.
Mishra A, Hogan SP, Brandt EB, Rothenberg ME. An etiological role for aeroallergens and eosinophils in experimental esophagitis. J Clin Invest. 2001 Jan;107(1):83-90.
NICHHD Pediatric Center for Gene Expression and Developmental Sciences. Training Director. National Institutes of Health. Dec 2011–Nov 2016. K12 HD028827.
Epithelial Genes in Allergic Inflammation. Co-Investigator. National Institutes of Health. Sep 2011–Aug 2016. U19 AI070235.
Eosinophil:M2 Macrophage:CCL11 Axis in Experimental Colitis and Pediatric Corticosteroid Resistant Ulcerative Colitis. Co-Investigator. National Institutes of Health. Apr 2012–Mar 2016. R01 DK090119-01A1.
Immunobiology of Peanut Allergy and It’s Treatment. Co-Investigator. National Institutes of Health. Jul 2010–Jun 2015. U19 AI066738.
Regulation of Gastrointestinal Eosinophils. Principal Investigator. National Institutes of Health. Dec 2009–Nov 2014. R37 AI045898.
Cincinnati Center for Clinical and Translational Science and Training. Co-Program Director. National Institutes of Health. Apr 2009–Mar 2015. KL2 TR000078.
The Expression and Function of Paired Immunoglobulin-like Receptor B in Eosinophils. Co-Principal Investigator. U.S. - Israel Binational Science Foundation. Oct 2012–Sep 2016. #201144.
Nancy M. Sawtell, PhD
Molecular mechanisms of herpes virus latency and reactivation; viral persistence; pathogenesis; animal models of disease
Visit the Sawtell Lab.
BA: Chemistry, Case Western Reserve University, 1975.
PhD: Pathology and Immunology, University of Cincinnati Medical College, Cincinnati, OH, 1986.
Farley N, Bernstein DI, Bravo FJ, Earwood J, Sawtell N, Cardin RD. Recurrent vaginal shedding of herpes simplex type 2 virus in the mouse and effects of antiviral therapy. Antiviral Res. 2010 May;86(2):188-95. Thompson RL, Preston CM, Sawtell NM. De novo synthesis of VP16 coordinates the exit from HSV latency in vivo. PLoS Pathog. 2009 Mar;5(3):e1000352. Currier MA, Gillespie RA, Sawtell NM, Mahller YY, Stroup G, Collins MH, Kambara H, Chiocca EA, Cripe TP. Efficacy and safety of the oncolytic herpes simplex virus rRp450 alone and combined with cyclophosphamide. Mol Ther. 2008 May;16(5):879-85. Thompson RL, Sawtell NM. Evidence that the herpes simplex virus type 1 ICP0 protein does not initiate reactivation from latency in vivo. J Virol. 2006 Nov;80(22):10919-30.
Sawtell NM, Thompson RL, Haas RL. Herpes simplex virus DNA synthesis is not a decisive regulatory event in the initiation of lytic viral protein expression in neurons in vivo during primary infection or reactivation from latency. J Virol. 2006 Jan;80(1):38-50. Sawtell NM. Detection and quantification of the rare latently infected cell undergoing herpes simplex virus transcriptional activation in the nervous system in vivo. Methods Mol Biol. 2005;292:57-72.
Sawtell NM, Thompson RL. Comparison of herpes simplex virus reactivation in ganglia in vivo and in explants demonstrates quantitative and qualitative differences. J Virol. 2004 Jul;78(14):7784-94.
Thompson RL, Shieh MT, Sawtell NM. Analysis of herpes simplex virus ICP0 promoter function in sensory neurons during acute infection, establishment of latency, and reactivation in vivo. J Virol. 2003 Nov;77(22):12319-30. Sawtell NM. Quantitative analysis of herpes simplex virus reactivation in vivo demonstrates that reactivation in the nervous system is not inhibited at early times postinoculation. J Virol. 2003 Apr;77(7):4127-38.
Sawtell NM, Thompson RL, Stanberry LR, Bernstein DI. Early intervention with high-dose acyclovir treatment during primary herpes simplex virus infection reduces latency and subsequent reactivation in the nervous system in vivo. J Infect Dis. 2001 Oct 15;184(8):964-71.
Daniel T. Starczynowski, PhD
Rhyasen GW, Bolanos L, Fang J, Jerez A, Wunderlich M, Rigolino C, Mathews L, Ferrer M, Southall N, Guha R, Keller J, Thomas C, Beverly LJ, Cortelezzi A, Oliva EN, Cuzzola M, Maciejewski JP, Mulloy JC, Starczynowski DT. Targeting IRAK1 as a Therapeutic Approach for Myelodysplastic Syndrome. Cancer Cell. 2013 Jul 8;24(1):90-104.
Guo F, Zhang S, Grogg M, Cancelas JA, Varney ME, Starczynowski DT, Du W, Yang JQ, Liu W, Zhu W, Thomas G, Kozma S, Pang Q, Zheng Y. Mouse gene targeting reveals an essential role of mTOR in hematopoietic stem cell engraftment and hematopoiesis. Haematologica. Epub. 2013 May 28.
Fang J, Rhyasen G, Bolanos L, Rasch C, Varney M, Wunderlich M, Goyama S, Jansen G, Cloos J, Rigolino C, Cortelezzi A, Mulloy JC, Oliva EN, Cuzzola M, Starczynowski DT. Cytotoxic effects of bortezomib in myelodysplastic syndrome/acute myeloid leukemia depend on autophagy-mediated lysosomal degradation of TRAF6 and repression of PSMA1. Blood. 2012 Jul 26;120(4):858-67.
Fang J, Varney M, Starczynowski DT. Implication of miRNAs in the pathogenesis of MDS. Current Pharmaceutical Design. 2012.
Vercauteren S, Starczynowski DT, Sung S, McNeil K, Salski C, Jensen C-L, Lam W, Karsan A. T cells of patients with Myelodysplastic syndrome are frequently derived from the malignant clone. British Journal of Haematology. Epub. 2011.
Starczynowski DT, Lockwood WL, Delehouzee S, Lam S, Tsao M-S, Gazdar AF, Lam W, Karsan A. TRAF6 is an amplified oncogene bridging the Ras and nuclear factor-kB cascade in lung cancer. Journal of Clinical Investigation. 2011 Oct;121(10):4095-105.
Rhyasen G, Starczynowski DT. Deregulation of microRNAs in Myelodysplastic Syndromes. Leukemia. 2011 Jan;26(1):13-22.
Kuchenbauer F, Mah SM, Heuser M, McPherson A, Ruschmann J, Rouhi A, Berg T, Bullinger L, Argiropoulos B, Morin RD, Lai D, Starczynowski DT, Karsan A, Eaves CJ, Watahiki A, Wang Y, Aparicio SA, Ganser A, Krauter J, Doehner H, Doehner K, Marra MA, Carmargo FD, Palmquist L, Buske C, Humphries RK. Comprehensive analysis of mammalian miRNA* species and their role in myeloid cells. Blood. 2011 Sep 22;118(12):3350-8.
Starczynowski DT, Vercauteren S, Sung S, Brooks-Wilson A, Lam WL, Karsan A. Copy number alterations at polymorphic loci may be acquired somatically in patients with myelodysplastic syndromes. Leuk Res. 2011 Apr;35(4):444-7.
Starczynowski DT, Kuchenbauer F, Wegrzyn J, Humphries K, Karsan A. Increased expression of microRNA-146 disrupts differentiation and survival of hematopoietic progenitor cells. Experimental Hematology. 2011 Feb;39(2):167-178.e4.
Susan Thompson, PhD
Molecular basis of juvenile rheumatoid arthritis; large-scale integrative analysis of gene expression, polymorphism and other genomic data with clinical data
Visit the Thompson Lab.
Susan Thompson, PhD, has research interests that span both genetic and functional genomic studies of juvenile rheumatoid arthritis (JRA) to advance the understanding of the causes and mechanisms of disease pathogenesis. A genome-wide screen for JRA susceptibility traits has been completed and defined several regions for linkage mapping and candidate gene analysis. In addition, complementary approaches that measure global gene expression patterns using DNA microarrays are also being used to understand the molecular basis for disease.
Thompson SD, Sudman M, Ramos PS, Marion MC, Ryan M, Tsoras M, Weiler T, Wagner M, Keddache M, Haas JP, Mueller C, Prahalad S, Bohnsack J, Wise CA, Punaro M, Zhang D, Rosé CD, Comeau ME, Divers J, Glass DN, Langefeld CD. The susceptibility loci juvenile idiopathic arthritis shares with other autoimmune diseases extend to PTPN2, COG6, and ANGPT1. Arthritis Rheum. 2010 Nov;62(11):3265-76.
Barnes MG, Grom AA, Thompson SD, Griffin TA, Luyrink LK, Colbert RA, Glass DN. Biologic similarities based on age at onset in oligoarticular and polyarticular subtypes of juvenile idiopathic arthritis. Arthritis Rheum. 2010 Nov;62(11):3249-58.
Thompson SD, Barnes MG, Griffin TA, Grom AA, Glass DN. Heterogeneity in juvenile idiopathic arthritis: impact of molecular profiling based on DNA polymorphism and gene expression patterns. Arthritis Rheum. 2010 Sep;62(9):2611-5.
Hinze CH, Fall N, Thornton S, Mo JQ, Aronow BJ, Layh-Schmitt G, Griffin TA, Thompson SD, Colbert RA, Glass DN, Barnes MG, Grom AA. Immature cell populations and an erythropoiesis gene-expression signature in systemic juvenile idiopathic arthritis: implications for pathogenesis. Arthritis Res Ther. 2010;12(3):R123.
Barnes MG, Grom AA, Thompson SD, Griffin TA, Pavlidis P, Itert L, Fall N, Sowders DP, Hinze CH, Aronow BJ, Luyrink LK, Srivastava S, Ilowite NT, Gottlieb BS, Olson JC, Sherry DD, Glass DN, Colbert RA. Subtype-specific peripheral blood gene expression profiles in recent-onset juvenile idiopathic arthritis. Arthritis Rheum. 2009 Jul;60(7):2102-12.
Griffin TA, Barnes MG, Ilowite NT, Olson JC, Sherry DD, Gottlieb BS, Aronow BJ, Pavlidis P, Hinze CH, Thornton S, Thompson SD, Grom AA, Colbert RA, Glass DN. Gene expression signatures in polyarticular juvenile idiopathic arthritis demonstrate disease heterogeneity and offer a molecular classification of disease subsets. Arthritis Rheum. 2009 Jul;60(7):2113-23.
Zhang K, Biroschak J, Glass DN, Thompson SD, Finkel T, Passo MH, Binstadt BA, Filipovich A, Grom AA. Macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis is associated with MUNC13-4 polymorphisms. Arthritis Rheum. 2008 Sep;58(9):2892-6.
Chaudhari M, Moroldo MB, Shear E, Hillard P, Thompson SD, Lan D, Huang B, Brunner HI, Glass DN. Impaired reproductive fitness in mothers of children with juvenile autoimmune arthropathies. Rheumatology (Oxford). 2006 Oct;45(10):1282-7.
Phelan JD, Thompson SD. Genomic progress in pediatric arthritis: recent work and future goals. Curr Opin Rheumatol. 2006 Sep;18(5):482-9. Phelan JD, Thompson SD, Glass DN. Susceptibility to JRA/JIA: complementing general autoimmune and arthritis traits. Genes Immun. 2006 Jan;7(1):1-10.
Stephen N. Waggoner, PhD
is a viral immunologist whose lab studies immune regulatory mechanisms that control pathogenesis of disease. We use viruses and bacteria to probe immune functions associated with disease in mice. Our interests currently focus on a novel regulatory role of natural killer (NK) cells that influences vaccine efficacy, autoimmune disease, chronic viral infections, and immune dysfunction in the elderly.
Viral immunology; natural killer cells; immunoregulation; vaccines; autoimmunity; immune dysfunction in aging.
Visit the Waggoner Lab.
Stephen Waggoner, PhD, is an assistant professor in the Center for Autoimmune Genomics and Etiology (CAGE) within the Division of Rheumatology at Cincinnati Children's Hospital Medical Center. Dr. Waggoner received his PhD from the University of Virginia, conducted postdoctoral research at the University of Massachusetts Medical School, and joined the faculty at Cincinnati Children’s in 2013. He has garnered international recognition for his discovery that natural killer (NK) cells play a crucial regulatory role during persistent virus infection involving suppression of virus-specific T cell responses. His lab continues to explore the relevance of this phenomenon to chronic infection, vaccine efficacy, autoimmune disease, and age-associated immune dysfunction.
BA: St. Mary's College of Maryland, St. Mary's City, MD, 2000.
PhD: University of Virginia, Charlottesville, VA, 2007.
Post Doc: University of Massachusetts Medical School, Worcester, MA.
Severa M, Islam SA, Waggoner SN, Jiang Z, Kim ND, Ryan G, Kurt-Jones E, Charo I, Caffrey DR, Boyartchuk VL, Luster AD, Fitzgerald KA. The transcriptional repressor BLIMP1 curbs host defenses by suppressing expression of the chemokine CCL8. The Journal of Immunology. 2014; 192(5):2291-304.
Waggoner SN, Daniels KA, Welsh RM. Therapeutic depletion of natural killer cells controls persistent infection. Journal of Virology. 2014; 88(4):1953-60.
Cornberg M, Kenney LL, Chen AT, Waggoner SN, Kim SK, Dienes HP, Welsh RM, Selin LK. Clonal exhaustion as a mechanism to protect against severe immuno-pathology and death from an overwhelming CD8 T cell response. Frontiers in Immunology. 2013; 4:475.
Welsh RM, Waggoner SN. NK cells controlling virus-specific T cells: Rheostats for acute vs. persistent infections. Virology. 2013; 435(1):37-45. Review.
Waggoner SN, Kumar V. Evolving role of 2B4/CD244 in T and NK cell responses during virus infection. Frontiers in Immunology. 2012; 3:377. Review.
Waggoner SN, Cornberg M, Selin LK, Welsh RM. Natural killer cells act as rheostats modulating anti-viral T cells. Nature. 2011; 481(7381):394-398.This paper is “Faculty of 1000 recommended.”
Rathinam VA, Jiang Z, Waggoner SN, Sharma S, Cole LE, Waggoner L, Vanaja SK, Monks BG, Ganesan S, Latz E, Hornung V, Vogel SN, Szomolanyi-Tsuda E, Fitzgerald KA. The AIM2 inflammasome is essential for host defense against cytosolic bacteria and DNA viruses. Nature Immunology. 2010; 11(5):395-402.This paper is “Faculty of 1000 recommended.”
Waggoner SN, Taniguchi RT, Mathew PA, Kumar V, Welsh RM. Absence of mouse 2B4 promotes NK cell–mediated killing of activated CD8+ T cells, leading to prolonged viral persistence and altered pathogenesis. Journal of Clinical Investigation. 2010; 120(6): 1925-38.
Waggoner SN, Hall CH, Hahn YS. HCV core protein interaction with gC1q receptor inhibits Th1 differentiation of CD4+ T cells via suppression of dendritic cell IL-12 production. Journal of Leukocyte Biology. 2007; 82(6):1407-1419.
Waggoner SN, Cruise MW, Kassel R, Hahn YS. gC1q receptor ligation selectively down-regulates human interleukin-12 production through activation of the phosphoinositide 3-kinase pathway. Journal of Immunology. 2005; 175(7):4706-4714.
Effect of aging on natural killer cell regulation of T cells in viral pathogenesis. Principal Investigator. Ellison Medical Foundation New Scholar in Aging. July 2012 - July 2016.
A revolutionary vaccine approach to prevent HIV infection in substance abuse. Principal Investigator. National Institute on Drug Abuse (NIDA) Avant-Garde Award For HIV/AIDS Research. June 2014-May 2019.
Yui-Hsi Wang, PhD
investigates the mechanisms that govern the plasticity of tissue resident TH2 memory / effector cells in the airway and gut. Particularly interested in understanding how inflammatory mediators, such as IL-1b, IL-33 and IL-25, regulate the development of IL-17-producing TH2 or IL-9-producing TH2 cells during airway or gastrointestinal allergic inflammation, respectively.
Wang YH, Voo KS, Liu B, Chen CY, Uygungil B, Spoede W, Bernstein JA, Huston DP, Liu YJ. A novel subset of CD4(+) T(H)2 memory/effector cells that produce inflammatory IL-17 cytokine and promote the exacerbation of chronic allergic asthma. J Exp Med. 2010 Oct 25;207(11):2479-91.
Shaw J, Wang YH, Ito T, Arima K, Liu YJ. Plasmacytoid dendritic cells regulate B-cell growth and differentiation via CD70. Blood. 2010 Apr 15;115(15):3051-7. Wang YH, Liu YJ. Thymic stromal lymphopoietin, OX40-ligand, and interleukin-25 in allergic responses. Clin Exp Allergy. 2009 Jun;39(6):798-806. Voo KS, Wang YH, Santori FR, Boggiano C, Wang YH, Arima K, Bover L, Hanabuchi S, Khalili J, Marinova E, Zheng B, Littman DR, Liu YJ. Identification of IL-17-producing FOXP3+ regulatory T cells in humans. Proc Natl Acad Sci U S A. 2009 Mar 24;106(12):4793-8. Lu N, Wang YH, Wang YH, Arima K, Hanabuchi S, Liu YJ. TSLP and IL-7 use two different mechanisms to regulate human CD4+ T cell homeostasis. J Exp Med. 2009 Sep 28;206(10):2111-9. Esashi E, Wang YH, Perng OA, Qin XF, Hennighausen L, Liu YJ, Watowich SS. Differential regulation of plasmacytoid and conventional dendritic cell development by GM-CSF through STAT5. Immunity. 2008;28:1-12. Wang YH, Liu YJ. The IL-17 cytokine family and their role in allergic inflammation. Curr Opin Immunol. 2008 Dec;20(6):697-702. Wang YH, Liu YJ. OX40-OX40L interactions: a promising therapeutic target for allergic diseases?J Clin Invest. 2007 Dec;117(12):3655-7.
Wang YH, Angkasekwinai P, Meng Q, Lu N, Voo KS, Arima K, Hanabuchi S, Corrigan CG, Lee T, Dong C, Huston DR, Yao Z, Ying S, and Liu YJ. IL-25 mediated cross talk between eosinophils and TSLP-DC-activated TH2 memory cells augments allergic immune responses. J. Exp. Med. 2007;204(8): 1837-1847. Ito T, Wang YH, Duramad O, Hanabuchi S, Perng OA, Gilliet M, Qin FX, Liu YJ. OX40 ligand shuts down IL-10-producing regulatory T cells. Proc Natl Acad Sci U S A. 2006 Aug 29;103(35):13138-43.
The roles of IL-17-producing TH2 memory/effector cells in allergic asthma. Principal Investigator. American Lung Association. July 2010 - June 2012. #AI-169584-N.
Regulation and maintenance of TH2 memory/effector cells. Principal Investigator. National Institutes of Health. May 2010- April 2015. #R01AI090129-01.
Sing Sing Way, MD, PhD Pauline and Lawson Reed Chair, Division of Infectious Diseases
is an infectious disease physician-scientist. He cares for infants and children with infection related illness, and provides consultation in the diagnosis and prevention diseases caused by communicable agents. Dr. Way supervises an active basic research laboratory that uses basic immunological approaches to investigate ways to boost host defense and protection against infection. If you have interest in this work, please contact Dr. Way.
Pauline and Lawson Reed Chair, Division of Infectious Diseases
Infectious diseases; prenatal infection; immunology
Dr. Way is an infectious disease physician-scientist. He cares for infants and children with infection related illness, and provides consultation in the diagnosis and prevention diseases caused by communicable agents. Dr. Way supervises an active basic research laboratory that uses basic immunological approaches to investigate ways to boost host defense and protection against infection. Ongoing projects investigate the immune basis responsible for enhanced susceptibility to infection during pregnancy, the immune pathogenesis of pregnancy complications that occur with maternal infection, and the basic signals required for stimulating immune cell activation.
Dr. Way trained in the combined MD/PhD program at the Albert Einstein College of Medicine, pediatric residency at the University of California San Francisco, and infectious disease fellowship at the University of Washington. During fellowship training, Dr. Way began investigating the basic immunology and immune pathogenesis of infectious diseases relevant to human, and in particular, infant and child health.
Dr. Way’s research has been supported by the National Institutes of Health since 2006. Dr. Way’s research has been described in many publications in numerous prestigious scientific journals including Nature, Cell Host & Microbe, PLoS Pathogens, and The Journal of Immunology. The past and ongoing work has also been recognized by numerous prestigious awards including the Infectious Diseases Society of America Wyeth Young Investigator Award, a Basil O’ Conner Award from the March of Dimes Foundation, and the Investigator in Pathogenesis of Infectious Diseases award from the Burroughs Wellcome Fund.
MD PhD: Albert Einstein College of Medicine, Bronx, NY, 1999.
Residency: University of California San Francisco, San Francisco, CA, 2001.
Fellowship: University of Washington, Seattle, WA, 2004.
Rowe JH, Ertelt JM, Xin L, Way SS. Pregnancy imprints regulatory memory that sustains anergy to fetal antigen. Nature. 490: 102-106. 2012.
Rowe JH, Ertelt JM, Xin L, Way SS. Listeria monocytogenes cytoplasmic entry induces fetal wastage by disrupting maternal Foxp3+ regulatory T cell-sustained fetal tolerance. PLoS Pathog. 8: e1002873. 2012.
Rowe JH, Ertelt JM, Way SS. Innate IFN-g is essential for Programmed death ligand-1-mediated T cell stimulation following Listeria monocytogenes infection. J Immunol. 189: 876-84. 2012.
Rowe JH, Ertelt JM, Way SS. Foxp3+ regulatory T cells, immune stimulation, and host defense against infection. Immunology. 136:1-10. 2011.
Ertelt JM, Johanns TM, Mysz MA, Nanton MR, Rowe JH, Aguilera MN, Way SS. Selective culling of high avidity antigen-specific CD4+ T cells after virulent Salmonella infection. Immunology. 134: 487-97. 2011.
Ertelt JM, Rowe JH, Mysz MA, Singh C, Roychowdhury M, Aguilera MN, Way SS. Foxp3+ regulatory T cells impede the priming of protective CD8+ T cells. J Immunol. 187: 2569-77. 2011.
Rowe JH, Ertelt JM, Aguilera MN, Farrar MA, Way SS. Foxp3+ regulatory T cell expansion required for sustaining pregnancy compromises host defense against prenatal bacterial pathogens. Cell Host Microbe. 10:54-64. 2011.
Johanns TM, Law CY, Kalekar LA, O’Donnell H, Ertelt JM, Rowe JH, Way SS. Early eradication of persistent Salmonella infection primes antibody-mediated protective immunity to recurrent infection. Microbes Infect. 13: 322-330. 2011.
Han JY, Hanson DC, Way SS. Herpes Zoster and meningitis due to reactivation of varicella vaccine virus in a immunocompetent child. Pediatr Infect Dis J. 30:266-268. 2011.
Ertelt JM, Johanns TM, Rowe JH, Way SS. IL-21-independent pathogen-specific CD8+ T cell expansion, and IL-21-dependnent suppression of CD4+ T cell IL-17 production. Immunology. 131: 183-191. 2010.
Maternal regulatory T cells control the immune pathogenesis of prenatal infection. Principal Investigator in the Pathogenesis of Infectious Disease. Burroughs Wellcome Fund. 2012-2017.
The immune pathogenesis of prenatal Listeria monocytogenes infection. Principle Investigator. National Institute of Allergy and Infectious Diseases (NIAID). 2012-2017. R01-AI100934.
Regulatory T cells dictate the immunity during persistent Salmonella infection. Principle Investigator. National Institute of Allergy and Infectious Diseases (NIAID). 2010-2015. R01-AI087830.
Timothy E. Weaver, MS, PhD Co-Director, Division of Pulmonary Biology
Co-Director, Division of Pulmonary Biology
Lung development; chaperone biology and diseases of protein misfolding; pulmonary fibrosis; asthma; respiratory distress syndrome; acute and chronic lung disease
Visit the Weaver Lab Site.
Dr. Weaver has a long-standing interest in lung development and disease. His early work with Dr. Whitsett uncovered the function of surfactant proteins SP-B and SP-C, a discovery that has profoundly influenced the treatment of respiratory distress syndrome and survival of pre-term infants worldwide. His current research is focused to the molecular pathways (ER stress and autophagy) that link mutations in the SFTPC gene (encoding surfactant protein C) to development of interstitial lung disease (ILD) in both children and adults. His work has been continuously funded by the National Institutes of Health since 1986, including a MERIT (R37) award from the National Heart, Lung and Blood Institute (2001-2011).
Dr. Weaver has trained 14 graduate students in the past 15 years and is the past director of the Molecular and Developmental Biology Graduate Program. During the same period of time he has trained 11 postdoctoral fellows, eight of whom are current faculty members at institutions in the US, Germany, France, Japan and UK.
BS: Biology, Bob Jones University, Greenville, South Carolina, 1975.
MS: Embryology, Hahnemann Medical College, Philadelphia, Pennsylvania, 1979. PhD: Developmental Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio, 1983.
Postdoc: Molecular Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio, 1986.
Hahn DR, Na CL, Weaver TE. Reserve autophagic capacity in alveolar epithelia provides a replicative niche for influenza A virus. Am J Respir Cell Mol Biol. 2014 Mar 24. Epub ahead of print.
Fritz JM, Dong M, Apsley KS, Martin EP, Na CL, Sitaraman S, Weaver TE. Deficiency of the BiP cochaperone ERdj4 causes constitutive endoplasmic reticulum stress and metabolic defects. Mol Biol Cell. 2014 Feb; 25(4):431-40.
Ridsdale R, Na CL, Xu Y, Greis KD, Weaver T. Comparative proteomic analysis of lung lamellar bodies and lysosome-related organelles. PLoS One.2011 26;6(1):e16482.
Yang L, Johansson J, Ridsdale R, Willander H, Fitzen M , Akinbi HT, Weaver TE. Surfactant Protein B Propeptide Contains a Saposin-Like Protein Domain with Antimicrobial Activity at Low pH. J Immunol. 2010 Jan 15;184(2):975-83.
Dong M, Bridges JP, Apsley K, Xu Y, Weaver TE. ERdj4 and ERdj5 Are Required for Endoplasmic Reticulum-associated Protein Degradation of Misfolded Surfactant Protein C. Mol Biol Cell. 2008 Jun;19(6):2620-30.
Korfei M, Ruppert C, Mahavadi P, Henneke I, Markart P, Koch M, Lang G, Fink L, Bohle RM, Seeger W, Weaver TE, Guenther A. Epithelial endoplasmic reticulum stress and apoptosis in sporadic idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2008 Oct 15;178(8):838-46.
Nash JA, Ballard TN, Weaver TE, Akinbi HT. The peptidoglycan-degrading property of lysozyme is not required for bactericidal activity in vivo. J Immunol. 2006 Jul 1;177(1):519-26.
Johansson H, Nordling K, Weaver TE, Johansson J. The Brichos domain-containing C-terminal part of pro-surfactant protein C binds to an unfolded poly-val transmembrane segment. J Biol Chem. 2006 Jul 28;281(30):21032-9.
Bridges JP, Xu Y, Na CL, Wong HR, Weaver TE. Adaptation and increased susceptibility to infection associated with constitutive expression of misfolded SP-C. J Cell Biol. 2006 Jan 30;172(3): 395-407.
Melton KR, Nesslein LL, Ikegami M, Tichelaar JW, Clark JC, Whitsett JA, Weaver TE. SP-B deficiency causes respiratory failure in adult mice. Am J Physiol Lung Cell Mol Physiol. 2003 Sep;285(3):L543-9.
Role of Autophagy in Pathogenesis of Interstitial Lung Disease. Principal Investigator. National Institutes of Health. Jul 2011 - Jun 2015. R01-HL103923.
Stard7, A Novel Inhibitor Of Allergic Lung Disease. Principal Investigator. National Institutes of Health. Dec 2013 - Nov 2017. R01-HL122130.
Matthew T. Weirauch, PhD
Transcription factors; transcriptional regulation; functional genomics; genome analysis; network-based algorithms; bioinformatics
Visit the Weirauch Lab
The staggering diversity of life on our planet stems from the elegant system encoded in our genomes. A major finding of the genomic era is that a substantial proportion of the wide range of biological form and function is likely explained by differences in gene regulation (the processes governing how and when genes are utilized), as opposed to differences in the genes themselves. An important component of gene regulation is the binding of transcription factors (TFs) to genomic DNA. A typical metazoan genome contains thousands of TFs, and knowledge of their sequence binding preferences is crucial to our understanding of the “regulatory code” governing health and disease.
Two major obstacles stand in our way before we can even begin to accurately model gene regulation. First, we must gain a thorough knowledge of the sequence binding preferences of TFs. Of an estimated 165,000 TFs present in the approximately 300 sequenced eukaryotic organisms, sequence preferences are currently known for only ~2,000 (~1%). In collaboration with Tim Hughes at the University of Toronto, I have developed a joint experimental and computational approach to determine or predict binding preferences for > 55,000 eukaryotic TFs (>30%), representing an order of magnitude improvement over our current knowledge. Second, there is an ongoing controversy surrounding the optimal way to represent TF binding preferences, and how to accurately model them to predict binding to genomic sequences. To address this issue, I have recently led the largest evaluation of computational TF binding models to date, involving 20 methods developed by researchers from around the world. Together, these two studies will provide the groundwork for the future development of models of gene regulation in both normal and disease states.
Postdoctoral Fellow: University of Toronto (Donnelly Center for Cellular and Biomolecular Research), Toronto, Ontario, Canada.
PhD: Bioinformatics, University of California Santa Cruz, Santa Cruz, California.
BSc: Computer Science, Pennsylvania State University, University Park, PA.
Weirauch M, Hughes T. A catalogue of eukaryotic transcription factor types, their evolutionary origin, and species distribution. Subcell Biochem. 2011;52:25-73. In: A Handbook of Transcription Factors, First Edition. Springer. Hughes, T, editor.
Weirauch M. Gene co-expression networks for the analysis of DNA microarray data. In: Applied Statistics for Network Biology: Methods in Systems Biology, First Edition. Wiley-VCH Verlag. Dehmer M, Emmert-Streib F, Graber A, Salvador A, editors. 2011.
Weirauch M, Hughes T. Dramatic changes in transcription factor binding over evolutionary time. Genome Biol. 2010 Jun 1;11(6):122.
Wang B, Kline C, Pastor D, Olson T, Frank B, Luu T, Sharma A, Robertson G, Weirauch M, Patierno S, Stuart J, Irby R, Lee N. Prostate apoptosis response protein 4 sensitizes human colon cancer cells to chemotherapeutic 5-FU through mediation of an NF kappaB and microRNA network. Mol Cancer. 2010 Apr 30;9:98.
Costanzo M, Baryshnikova A, Bellay J, Kim Y, Spear E, Sevier C, Ding H, Koh J, Toufighi K, Mostafavi S, Prinz J, St Onge R, VanderSluis B, Makhnevych T, Vizeacoumar F, Alizadeh S, Bahr S, Brost R, Chen Y, Cokol M, Deshpande R, Li Z, Lin Z, Liang W, Marback M, Paw J, San Luis B, Shuteriqi E, Tong A, van Dyk N, Wallace I, Whitney J, Weirauch M, Zhong G, Zhu H, Houry W, Brudno M, Ragibizadeh S, Papp B, Pál C, Roth F, Giaever G, Nislow C, Troyanskaya O, Bussey H, Bader G, Gingras A, Morris Q, Kim P, Kaiser C, Myers C, Andrews B, Boone C. The genetic landscape of a cell. Science. 2010 Jan 22;327(5964):425-31.
Weirauch M, Hughes T. Conserved expression without conserved regulatory sequence: the more things change, the more they stay the same. Trends Genet. 2010 Feb;26(2):66-74.
Weirauch M, Wong C, Byrne A, Stuart J. Information-based methods for predicting gene function from systematic gene knock-downs. BMC Bioinformatics. 2008 Oct 29;9:463.
Byrne A, Weirauch M, Wong V, Koeva M, Dixon S, Stuart J, Roy P. A global analysis of genetic interactions in Caenorhabditis elegans. J Biol. 2007;6(3):8.
ENCODE Project Consortium. Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature. 2007 Jun 14;447(7146):799-816.
Chen C, Weirauch M, Powell C, Zambon A, Stuart J. A search engine to identify new pathway genes from expression data on multiple organisms. BMC Systems Biology. 2007 May 4;1(1):20.
Susanne Wells, PhD Director, Epithelial Carcinogenesis and Stem Cell Program
Director, Epithelial Carcinogenesis and Stem Cell Program
Director, Postdoctoral Office
Squamous cell carcinoma; mechanisms by which the HPV oncogenes subvert the host cell machinery to promote abnormal cell growth and cancer; role of specific cellular HPV targets in viral replication and cellular transformation
Visit the Wells Lab.
Susanne Wells graduated from the University of Konstanz, Germany, with a degree in Biology. She completed her PhD in Molecular Biology at the State University of Stony Brook, NY, and her Postdoctoral Fellowship at Harvard Medical School, MA. Dr. Wells moved to Cincinnati Children's Hospital Medical Center in 2002 to study human papillomavirus infection and associated carcinogenesis.
Bahassi, M., Li, Y-Q, Wise-Draper, T. M., Deng, L., Wang, J., Colleen, D., Wilson, K. M., Wells, S. I., Stambrook, P. J. Rixe,0. 2013. A somatic mutation in the EGFR ligand-binding domain is associated with increased sensitivity to cetuximab. European J. Cancer, in press
Privette Vinnedge, L. M., Ho,S.-M., Wikenheiser-Brokamp, K. A., Wells, S. I. 2012. The DEK oncogene is a target of steroid hormone receptor signaling in breast cancer. PLOS One. 7(10):e46985. doi: 10.1371.
Hoskins, E. E., Morreale, R. J., Werner, S. P., Higginbotham, J. M., Laimins, L.A., Lambert, P. F., Brown, D. R., Gillison, M. L., Nuovo, G. J., Witte, D.P., Kim, M-O, Davies, S.M., Mehta, P. A., Butsch Kovacic, M., Wikenheiser-Brokamp, K. A., Wells, S. I. 2012. The Fanconi anemia pathway limits human papillomavirus replication. Journal of Virology. 86; 8131- 8138.
Wise-Draper, T. M., Draper, D. J., Gutkind, J. S., Molinolo, A. A., Wikenheiser-Brokamp, K. A., and Wells, S. I., 2012. Future directions and treatment strategies for head and neck squamous cell carcinomas. Transl. Res. 160; 167-177.
Morrison, M.A., Morreale, R. J., Akunuru, S., Kofron, M., Zheng, Y., Wells, S. I. 2011. Targeting the human papillomavirus E6 and E7 oncogenes through expression of the BPV1 E2 protein stimulates cellular motility. Jo