? ? This proposal describes a five-year training program for the development of an academic career in transfusion medicine and coagulation. The principal investigator has completed a formal residency program in clinical pathology and is currently a transfusion medicine fellow at the University of Pennsylvania. His research interests lie in immunohematology, hemostasis, and thrombosis, both clinically and at a basic research level. He will conduct the proposed research project under the sponsorship of Dr. Don Siegel, an expert in the application of phage display technologies in immunohematology and Dr. Douglas Cines, a leader in vascular biology and autoimmune thrombocytopenias. The principal investigator's proposal is enthusiastically supported by his Advisory Committee, whose members command an in-depth expertise in transgenic mouse models of thrombosis, immunohematology, and platelet biology. ? ? Heparin-induced thrombocytopenia/thrombosis (HIT/HITT) is the most frequent cause of drug-induced antibody-mediated thrombocytopenia and a common cause of life- and limb-threatening thrombosis. The initiating event in HITT is the interaction of pathogenic antibodies towards a complex of Platelet Factor 4 (PF4) and heparin (PF4:H). These immune complexes are believed to activate human platelets in vivo via RcyRIIA, leading to platelet activation, microparticle release, and platelet-platelet and platelet-vessel wall interactions, which predisposes to thrombosis. This proposal aims to clone and characterize human PF4:H antibodies and their binding sites and represents a comprehensive genetic investigation of a hapten-protein autoimmune response in otherwise healthy human beings. Characterizing these pathogenic antibodies on a molecular genetic level will facilitate the design of potentially therapeutic peptidomimetics and recombinant antibody fragments that can block the effects of pathogenic anti-PF4:H antibodies and the clinical features of HITT in our transgenic murine models of HITT. ? ? The intellectual strength and academic track-record of the sponsors and Advisory Committee, the expertise in novel molecular methods, the availability of all necessary reagents and equipment, and the quality of the research facilities makes the Department of Pathology and Laboratory Medicine at the University of Pennsylvania the ideal environment to conduct the proposed training program. ? (End of Abstract) ? ? ? ?
| Chen, Michael L; Logan, T Daniel; Hochberg, Maryann L et al. (2009) Erythroid dysplasia, megaloblastic anemia, and impaired lymphopoiesis arising from mitochondrial dysfunction. Blood 114:4045-53 |
