Qishen Pang, PhD
Identification of leukemia-initiating cells (LICs) in FA AML patients and FA mice – We recently demonstrated that interleukin-3 receptor a (IL-3Ra) is a promising candidate as an LIC-specific antigen for FA AML. We are in the process of studying FA mouse LIC functionality using bone marrow transplantation assays.
Qishen Pang, PhD
Studies of the role of FA proteins in protecting anti-oxidant genes from oxidative damage. – We showed that certain important genes functioning in anti-oxidant defense and reactive oxygen species (ROS) metabolism were significantly downregulated in FA samples compared to those of normal donors. We then demonstrated a novel role for the FA pathway in cellular antioxidant defense.
Qishen Pang, PhD
Studies of the natural antioxidant Salidroside in HSC maintenance. – Using several mouse models deficient for DNA repair pathways (including the FA pathway) known to be involved in oxidative DNA damage repair, we demonstrate that Salidroside protects quiescent HSPCs from oxidative stress-induced cycling through stimulation the activity of poly(ADP-ribose)polymerase-1 (PARP-1), a component of the base excision repair pathway.
Nancy Ratner, PhD
Hennigan et al. showed that the NF2 tumor suppressor regulates microtubule –based vesicle trafficking via the novel Rac, MLK and p38SAPK pathway.
Yi Zheng, PhD
We have published a series of studies related to rational design, screening and validation of lead inhibitors targeting RhoA GTPase and NOX2 enzymes, defining the pathologic roles of GTPases RhoA, Rac1 and Cdc42 in cancer and blood diseases, and revealing the essential signaling pathways of Rho GTPases in neural, eye, heart, and blood development.
Jose Cancelas, MD, PhD
Our research focus is on intrinsic and extrinsic (microenvironment) signals controlling stem cell function in hematopoietic tissues and in leukemia. Specific projects include: Rac GTPases inhibition in chronic myelogenous leukemia, Vav / Rac as a molecular target in pediatric acute lymphoblastic leukemia, and connexin-43 in bone marrow failure after cancer-related chemotherapy.
We have made progress in understanding the molecular mechanisms of Neurofibroma tumorigenesis under neurofibromatosis type 1, and established a preclinical therapeutic testing of neurofibroma in mouse.
With collaboration with Dr. Clinton Joiner's group under NIH Sickle Cell Center, we co-published our study on K-Cl cotransporter gene expression during human and murine erythroid differentiation on JBC. Our study on the application of secreted Gaussia luciferase (Gluc) as a marker for in vivo bioluminescent monitoring of system protein delivery, as well as its natural biodistribution in mice has been published on Molecular Biotechnology.
The Andreassen lab has discovered that a ubiquitin-dependent signaling pathway, involving the RNF8 E3 ubiquitin ligase and the RAP80 ubiquitin-binding protein, recruits the core machinery for homologous recombination to sites of DNA damage through PALB2.
The overarching goal of the research program of Dr Filippi’s lab is to understand the molecular regulation of hematopoietic cell functions. Specifically, we have been investigating the role of cell shape and cytoskeleton reorganization in modulating hematopoietic stem cell self renewal and engraftment, and neutrophil migration and trafficking. To do so, we are using genetics knock out animal models of regulators of cytoskeleton, namely Rho GTPases, and state of the art microscopy techniques, including live cell imaging, and immunofluorescence microscopy and multispectral imaging flow cytometry (Amnis ImageStream). Recent major findings from our work is the identification of a new role for p190-B-RhoGAP as a regulator of hematopoietic stem cell self renewal and cell fate decision during cell division. Furthermore, we are now showing that p190-B does so by regulating cell shape and polarity that ultimately influences the balance of asymmetric/symmetric self renewal. Other research project is to dissect the process of cell migration in neutrophils. We have made majors contribution to this field. Notably, we recently showed that Cdc42 unexpectedly uses aMb2 integrin signaling for efficient directed migration. A further understanding of the mechanism underlying these functions may lead to novel protocol of stem cell expansion ex vivo and novel therapeutic approach to neutrophilic inflammation, respectively.
We have made progress in studying the role of mTOR in stem cell/ progenitor cell differentiation, and in defining the role of Cdc42 and RhoA GTPases in T cell activation.
Dissection of the molecular pathogenesis of MLL-fusion AML and AML1-ETO-associated AML. Showed the importance of the Rac/Bcl family of proteins in MLL-fusion AML and the possibility of targeting these proteins therapeutically. Defined the role that Thrombopoeitic/MPL/Bcl-xL plays downstream of the AML1-ETO oncogene.
We performed an shRNA screen to identify modifiers of Lenalidomide, characterized movel TRAF6 transgenic knockout and overexpression mice, characterized a novel TIFAB knockout mouse, developed a novel xenograft model using MDS-derived patient cells. A research paper accepted on novel mechanisms of Bortezomib, and another research paper is being prepared for submission on targeting IRAK1 in MDS.
I have made progress in developing gene therapy for patients with genetic diseases that are treatable through hematopoietic stem cell based therapies, developing iPSC lines from patient specific induced pluripotent stem cells to study the cell physiology of the disease and develop therapies, and designing new cell therapies for disease.
We are currently writing two manuscripts: One describing the effect of Shp2 (PTPN11) mutations on brain development, specifically in the development of myelinating oligodendrocytes. These findings are significant because Shp2 is mutated in the RAS related disorders, Noonan and LEOPARD syndrome. Patients in both of these syndromes exhibit neurocognitive defects. We hope to understand the neurodevelopmental abnormalities that occur when Shp2 mutations are expressed and that this will provide evidence towards the developmental basis of the behavioral phenotypes. The other manuscript is identifying the role of the Zic genes, which are zinc-finger transcription factors, in the forebrain. We have identified that a mouse model of Dandy-Walker syndrome (Zic1/4+/-) exhibits midline forebrain defects. This is significant because only cerebellar defects have been described in previous studies with this mouse.
My Lab has been awarded 2 large new contracts for work supporting gene transfer trials. This new work allows us to hire more staff and expand our services.
Johannes C.M. van der Loo
Contract manufacturing of research-grade and clinical grade viral vectors based on a fee-for-service model to support investigators locally, nationally and internationally with materials to support their research and phase I/II clinical trials.
We report the isolation and characterization of a novel 20-kDa FANCA-associated protein (FAAP20). We show that FAAP20 is an integral component of the FA nuclear core complex. We identify a region on FANCA that physically interacts with FAAP20, and show that FANCA regulates stability of this protein. FAAP20 contains a conserved ubiquitin-binding zinc-finger domain (UBZ), and binds K-63-linked ubiquitin chains in vitro. The FAAP20-UBZ domain is not required for interaction with FANCA, but is required for DNA-damage-induced chromatin loading of FANCA and the functional integrity of the FA pathway. These findings reveal critical roles for FAAP20 in the FA-BRCA pathway of DNA damage repair and genome maintenance.
We are interested in computational and experimental analyses of global molecular networks supporting tumorigenesis. Projects in the lab include development of novel computational tools and their use in integrated analyses of drug resistance networks alongside with experimentation.
Continued analysis of the pathogenesis of inflammatory arthritis including a publication highlighting the use of a novel targeting-agent with potential efficacy for diagnostic imaging and drug delivery. A new project has been initiated, funded by a Cincinnati Children's Hospital Medical Center DHC pilot and feasibility grant, to study the mechanisms by which coagulation factors drive the pathogenesis of fatty liver disease.
Dr. J. L. Degen presented a “State-of-the-Art” lecture on Hemostatic Factors in Cancer at the American Society of Hematology (ASH) Conference in San Diego, December 10, 2011, as well as presented the Simon Karpatkin Memorial Lecture at the 6th International Conference on Thrombosis and Hemostasis Issues in Cancer, in Bergamo, Italy, April 20, 2012. In collaborative studies with investigators at the Rockefeller University, Dr. J. L. Degen’s laboratory has developed new insights into the cellular sources and biological importance of TGF-b1, a cytokine known to control cell proliferation, differentiation, immune cell function and thromboinflammatory disease process. Detailed studies reported in Blood of mice engineered to specifically lack platelet-derived TGF-b1 revealed that platelets contain the vast majority (>95%) of circulating TGF-b1, but the loss of platelet TGF-b1 does not alter hemostatic function in vivo. However, mice lacking platelet-derived TGF-b1 were found to be protected from the development of cardiac hypertrophy, fibrosis, and systolic dysfunction following a pressure overload challenge. Together with Dr. Punam Malik, interventions at the level of platelet-derived TGF-b1 are currently being explored as means of limiting cardiovascular pathologies associated with sickle cell disease.
My research focuses on understanding the structure/function relationship of signaling proteins involved in cancer propagation and initiation and on finding ways to inhibit them by targeted rational drug design. More specifically, we are targeting oncogenic Ras in cancer.
The Kalfa lab had a significant publication in Blood demonstrating that erythroblast enucleation is a more complex process than previously thought requiring a multistep action of tubulin and filamentous actin, as well as lipid raft formation coordinated by Rac GTPases.
The Chow lab is studying a form of aggressive brain tumor called high-grade glioma. Using novel mouse models for this disease, we are investigating the molecular characteristics of different tumor subgroups as well as distinguishing features of invasive disease, which is responsible for treatment failure and patient mortality. We are also using these models to develop novel therapeutic approaches for this disease.
Our work demonstrating that Rac GTPase survival signaling through Bcl-2 proteins may be therapeutically targeted in MLL fusion-mediated acute myeloid leukemia was published in the journal Blood.
Gene expression analysis of primary and secondary hemophagocytic lymphohistiocytosis. Molecular analysis of fusion oncogenes and their products in pediatric soft tissue sarcomas.
We will be starting the clinical trial for gene therapy for Sickle Cell Disease. We have also began working on gene therapy for HLH with Drs. Jordan and Risma. A clinical trial for Sickle Nephropathy has begun.