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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
Assistant Professor, Genetics and Allergy & Immunology
Assistant Professor, Genetics and Allergy & Immunology
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 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
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, Division of Pediatric 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
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.
Rac GTPase Inhibition in Chronic Myelogenous Leukemia. Principal Investigator. National Institutes of Health. Apr 2009 – Feb 2014. #R01 HL 087159.
Improving Hematopoietic Stem Cell Mobilization by the EGFR inhibitor Erlotinib. Co-Principal Investigator with Hartmut Geiger. NIH/NHLBI. Feb 2011 – Jan 2013. #R43HL108403-01.
Connexin-43 in Bone Marrow Failure After Cancer-Related Chemotherapy. Principal Investigator. Heimlich Institute. Apr 2010 – Mar 2013.
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.
Associate Professor, UC Department of Pediatrics
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.
Homeostasis and function of regulatory T cells in aging. National Institutes of Health. Sep 2009 - Sep 2011. #R01 AG033057 ARRA.
Dysfunction in biliary atresia. National Institutes of Health. Aug 2003 - Dec 2011. #R01 DK 065008.
Late Preterm Birth, Ureaplasma Species and Childhood Lung Disease. National Institutes of Health. Aug 2009 - Jul 2013. #R01 HL097064-01.
George Deepe, MD
Host response to fungi
Kroetz DN, Deepe GS Jr. An aberrant thymus in CCR5-/- mice is coupled with an enhanced adaptive immune response in fungal infection. J Immunol. 2011 May 15;186(10):5949-55. Szymczak WA, Deepe GS Jr. Antigen-presenting dendritic cells rescue CD4-depleted CCR2-/- mice from lethal Histoplasma capsulatum infection. Infect Immun. 2010 May;78(5):2125-37.
Kroetz DN, Deepe GS Jr. CCR5 dictates the equilibrium of proinflammatory IL-17+ and regulatory Foxp3+ T cells in fungal infection. J Immunol. 2010 May 1;184(9):5224-31.
Szymczak WA, Deepe GS Jr. The CCL7-CCL2-CCR2 axis regulates IL-4 production in lungs and fungal immunity. J Immunol. 2009 Aug 1;183(3):1964-74.
McCormack FX, Gibbons R, Ward SR, Kuzmenko A, Wu H, Deepe GS Jr. Macrophage-independent fungicidal action of the pulmonary collectins. J Biol Chem. 2003 Sep 19;278(38):36250-6.
Gomez FJ, Woodward EO, Pilcher-Roberts R, Gibbons RS, Deepe GS Jr. V beta 6+ and V beta 4+ T cells exert cooperative activity in clearance of secondary infection with Histoplasma capsulatum. J Immunol. 2001 Feb 15;166(4):2855-62.
Allendoerfer R, Deepe GS Jr. Regulation of infection with Histoplasma capsulatum by TNFR1 and -2. J Immunol. 2000 Sep 1;165(5):2657-64.
Deepe GS Jr, Gibbons R, Woodward E. Neutralization of endogenous granulocyte-macrophage colony-stimulating factor subverts the protective immune response to Histoplasma capsulatum. J Immunol. 1999 Nov 1;163(9):4985-93.
Allendörfer R, Brunner GD, Deepe GS Jr. Complex requirements for nascent and memory immunity in pulmonary histoplasmosis. J Immunol. 1999 Jun 15;162(12):7389-96.
Gomez FJ, Cain, JA, Gibbons R, Allendoerfer R, and Deepe GS, Jr. Vβ4+T cells exert protection in murine in pulmonary histoplasmosis. J Clin Invest. 1998;102:984-995.
GM-CSF Regulation of Zinc in Histoplasmosis. Principal Investigator. National Institutes of Health. Feb 2011 - Feb 2013.
Immunopathogenesis in Histoplasmosis. Principal Investigator. National Institutes of Health. Jun 2008 - May 2013.
Molecular and Cellular Determinants of Immunity in Histoplasmosis. Principal Investigator. Veterans Affairs. Apr 2010 - Mar 2014.
Chemokine-Cytokine Nexus in Fungal Immunity. Principal Investigator. National Institutes of Health. Feb 2010 - Jan 2015.
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.
Hemostatic factors as determinants of bacterial virulence and host defense. Principal Investigator. National Heart, Lung and Blood Institute. Sep 2006 – Aug 2011. #R01 HL085357.
Thrombin-mediated proteolysis in neuroinflammatory disease. Principal Investigator. National Heart, Lung and Blood Institute. Jul 2009 – Jun 2014. #R01 HL096126.
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
I am 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 my post-doc in the laboratory of Dr David Williams, we 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, we 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, we 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. My 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.
Pathogenesis and prevention of anaphylaxis induced by ingested antigens. Veterans Association. National Institutes of Health. Apr 2008 - Mar 2012.
IgG isotype regulation of antibody-mediated disorders. Principal Investigator. National Institutes of Health. Oc 2009 - Aug 2012.
Alternative macrophage activation limits immunopathology. Co-principal Investigator. National Institutes of Health. Dec 2007 - Nov 2012.
Multidisciplinary clinical research center in Cincinnati Project 2 - Improved understanding of the biology and use of TNF inhibition in JIA. Co-principal Investigator. National Institutes of Health. Apr 2008 - Mar 2013.
Regulation of CD8+ T cell homeostasis by IL-4. Principal Investigator. National Institutes of Health. Oct 2008 - Dec 2013.
IL-13 associated eosinophil lung responses. Co-principal Investigator. National Institutes of Health. Jul 2009 - Jun 2014.
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.
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.
Coagulation factors and the pathogenesis of non-alcoholic fatty liver disease. Principle Investigator. Cincinnati Children’s Hospital Digestive Health Center (DHC) Pilot and Feasibility Grant. Jun 2012 - May 2013. P30 DK078392.
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 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
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.
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.
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.
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.
Phelan JD, Shroyer NF, Cook T, Gebelein B, Grimes HL. Gfi1-cells and circuits: unraveling transcriptional networks of development and disease. Curr Opin Hematol. 2010 Jul;17(4):300-7. Review.
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.
Guo F, Velu CS, Grimes HL, Zheng Y. Rho GTPase Cdc42 is essential for B-lymphocyte development and activation. Blood. 2009 Oct 1;114(14):2909-16.
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.
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.
John B. Harley, MD, PhD
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.
Molecular & Immunologic Analysis of the Pathobiology of Human Anthrax. Co-Principal Investigator. National Institute of Allergy and Infectious Diseases. Sep 2009 - Aug 2014. #AI062629-06.Genomics of Lupus. Principal Investigator. Aug 2009 - Jul 2014. #1 P01 AI083194-01.Oklahoma Autoimmunity Center of Excellence Project 2. Co-investigator. National Institute of Allergy and Infectious Diseases. May 2009 - Apr 2014. #1 U19 AI082714-01.
Genome-Wide Association Study in African-Americans with Systemic Lupus Erythematosus. Principal Investigator. Department of Defense. Sep 2010- Aug 2013. #PR094002.Genomics of Lupus Associations in the Hispanic 12q24 Linkage. Principal Investigator. National Institutes of Health. Jun 2008 - Mar 2013. #5 P01 AR049084-07.Lupus Association with Signal Transducer and Activator of Transcription 4. Principal Investigator. US Department of Veterans Affairs. Apr 2008 - Mar 2012.
Genetic Linkage in Lupus. Principal Investigator. National Institute of Allergy and Infectious Diseases. Feb 2010 - Jan 2012. #3 R37 AI024717-21S1.
Andrew Herr, PhD
Biophysical and crystallographic studies of cellular adhesion and receptor signaling
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.
Director, Division of Asthma Research
Asthma; allergic rhinitis; food allergy; urticaria
Genetics of allergy and asthma; cytokines; signaling pathways
Khurana Gurjit 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 Associate Director of the Physician 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. She is the Principal Investigator of an NIH-funded Asthma and Allergic Diseases Cooperative Research Center (AADCRC) and serves on the AADCRC steering committee. This Center is focused on characterizing epithelial genes in allergic diseases, and delineating the mechanisms by which they contribute to the allergic response. She is also a co-investigator of the NIEHS-funded Cincinnati Childhood Asthma and Air Pollution Study, a birth cohort study designed to elucidate gene:environment interactions relevant to the development of allergic disease in early life. In addition to her research contributions, she is an outstanding clinician and teacher/mentor. Several of her trainees now hold academic faculty positions.
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 and is the Chair of the Genetics, Molecular Biology, and Epidemiology Committee. She serves on the Editorial Board of the Journal of Allergy and Clinical Immunology and on a regular NIH study section. 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.
Le Cras TD, Acciani TH, Mushaben EM, Kramer EL, Pastura PA, Hardie WD, Korfhagen TR, Sivaprasad U, Ericksen M, Gibson AM, Holtzman MJ, Whitsett JA, Khurana Hershey GK. Epithelial EGF receptor signaling mediates airway hyperreactivity and remodeling in a mouse model of chronic asthma. Am J Physiol Lung Cell Mol Physiol. 2011 Mar;300(3):L414-21.
Baye TM, Butsch Kovacic M, Biagini Myers JM, Martin LJ, Lindsey M, Patterson TL, He H, Ericksen MB, Gupta J, Tsoras AM, Lindsley A, Rothenberg ME, Wills-Karp M, Eissa NT, Borish L, Khurana Hershey GK. Differences in Candidate Gene Association between European Ancestry and African American Asthmatic Children. PLoS One. 2011 Feb 28;6(2):e16522.
Cortina SD, Drotar D, Ericksen M, Lindsey M, Patterson TL, Biagini Myers JM, Kovacic MB, Khurana Hershey GK. Genetic Biomarkers of Health-Related Quality of Life in Pediatric Asthma. J Pediatr. 2011 Feb 14.
Epstein TG, Bernstein DI, Levin L, Khurana Hershey GK, Ryan PH, Reponen T, Villareal M, Lockey JE, Lemasters GK. Opposing effects of cat and dog ownership and allergic sensitization on eczema in an atopic birth cohort. J Pediatr. 2011 Feb;158(2):265-271.e5.
Newcomb DC, Boswell MG, Zhou W, Huckabee MM, Goleniewska K, Sevin CM, Khurana Hershey GK, Kolls JK, Peebles RS Jr. Human T(H)17 cells express a functional IL-13 receptor and IL-13 attenuates IL-17A production. J Allergy Clin Immunol. 2011 Jan 12.
Sivaprasad U, Askew DJ, Ericksen MB, Gibson AM, Stier MT, Brandt EB, Bass SA, Daines MO, Chakir J, Stringer KF, Wert SE, Whitsett JA, Le Cras TD, Wills-Karp M, Silverman GA, Khurana Hershey GK. A nonredundant role for mouse Serpinb3a in the induction of mucus production in asthma. J Allergy Clin Immunol. 2011 Jan;127(1):254-61, 261.e1-6.
Sivaprasad U, Warrier MR, Gibson AM, Chen W, Tabata Y, Bass SA, Rothenberg ME, Khurana Hershey GK. IL-13Rα2 has a protective role in a mouse model of cutaneous inflammation. J Immunol. 2010 Dec 1;185(11):6802-8.
Biagini Myers JM, Khurana Hershey GK. Eczema in early life: genetics, the skin barrier, and lessons learned from birth cohort studies. J Pediatr. 2010 Nov;157(5):704-14.
Baye TM, Martin LJ, Khurana Hershey GK. Application of genetic/genomic approaches to allergic disorders. J Allergy Clin Immunol. 2010 Sep;126(3):425-36; quiz 437-8.
Codispoti CD, Levin L, LeMasters GK, Ryan P, Reponen T, Villareal M, Burkle J, Stanforth S, Lockey JE, Khurana Hershey GK, Bernstein DI. Breast-feeding, aeroallergen sensitization, and environmental exposures during infancy are determinants of childhood allergic rhinitis. J Allergy Clin Immunol. 2010 May;125(5):1054-1060.e1.
David A. Hildeman, PhD
Director, Immunobiology Graduate Program
Director, Immunobiology 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.
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.
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 Admissions, Immunobiology Graduate Program
Director of Admissions, Immunobiology Graduate Program
Allergies; food allergies; eosinophil biology; gastrointestinal inflammation
Visit the Hogan Lab.
Munitz A, Cole ET, Beichler 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 Aug;139(2):530-41.
Osterfeld H, Ahrens R, Strait R, Finkelman FD, Renauld JC, Hogan SP. Differential roles for the IL-9/IL-9 receptor alpha-chain pathway in systemic and oral antigen-induced anaphylaxis. J Allergy Clin Immunol. 2010 Feb;125(2):469-476.e2.
Finkelman FD, Hogan SP, Hershey GK, Rothenberg ME, Wills-Karp M. Importance of cytokines in murine allergic airway disease and human asthma. J Immunol. 2010 Feb 15;184(4):1663-74. Review.
Groschwitz KR, Ahrens R, Osterfeld H, Gurish MF, Han X, Abrink M, Finkelman FD, Pejler G, Hogan SP. Mast cells regulate homeostatic intestinal epithelial migration and barrier function by a chymase/Mcpt4-dependent mechanism. Proc Natl Acad Sci U S A. 2009 Dec 29;106(52):22381-6.
Herbert 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.
Groschwitz KR, Hogan SP. Intestinal barrier function: molecular regulation and disease pathogenesis. J Allergy Clin Immunol. 2009 Jul;124(1):3-20; quiz 21-2. Review.
Munitz A, Seidu L, Cole ET, Ahrens R, Hogan SP, Rothenberg ME. Resistin-like molecule alpha decreases glucose tolerance during intestinal inflammation. J Immunol. 2009 Feb 15;182(4):2357-63.
Hogan SP. Functional role of eosinophils in gastrointestinal inflammation. Immunol AllergyClin North Am. 2009 Feb;29(1):129-40, xi. Review.
Munitz A, Waddell A, Seidu L, Cole ET, Ahrens R, Hogan SP, Rothenberg ME. Resistin-like molecule alpha enhances myeloid cell activation and promotes colitis. J Allergy Clin Immunol. 2008 Dec;122(6):1200-1207.e1.
Ahrens R, Waddell A, Seidu L, Blanchard C, Carey R, Forbes E, Lampinen M, Wilson 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. J Immunol. 2008 Nov 15;181(10):7390-9.