This is a competitive renewal application for years 11-15 of a Program Project Grant providing support for a coordinated, multi-disciplinary investigation of molecular and cellular mechanisms of molecular and cellular mechanisms that are important to the field of transfusion medicine-a discipline that, despite its obvious importance to the nation's health, has historically been under-represented in both human and financial resources. Our current proposal reflects the continuing evolution of the Project Leaders' common interests in both basic and clinical problems facing the transfusion sciences, and takes advantage of technological advances that now enable many of the Projects within our Program to shift their emphasis from cell culture systems to in vivo models of blood and vascular cell physiology. We enter this period with a group of dedicated Project Leaders committed to interrelated research projects centered around the biology of blood and vascular cells. The project of Peter Neuman seeks to examine molecular mechanisms of platelet activation and adhesion through the development of murine models of platelet-mediated thrombosis and hemorrhage. The ability of a newly identified member of the Inhibitory Receptor family, PECAM-1, to modulate platelet activation and integrin function, will also be explored. The project of Jack Gorski seeks to investigate mechanisms underlying the immune response to clinically important human platelet alloantigens, and proposes a series of investigations designed to test a novel model of alloimmunity. The Project of Dick Aster explores the etiology of immune thrombocytopenias in patients undergoing anti-platelet therapy with Fibrinogen Receptor Antagonists. Cheryl Hillery's project employs a genetic and pharmacologic approach to explore the relative contributions of fibrin formation and platelet activation to the development of vaso- occlusion in a murine model of sickle cell diseases. Bob Montgomery's project continues to explore the impact of structural and functional alterations of vWF on its intracellular processing and trafficking, and additionally proposes to elucidate the role of vWF as an intracellular chaperone for blood coagulation factor VIII. The Administrative Core will oversee and coordinate the day-to-day scientific and fiscal operation of the Program. The Shared Instrumentation Core will continue to provide centralized instrumentation and expertise for DNA sequence analysis, peptide and oligonucleotide synthesis, microscopy/digital image analysis, flow cytometry and cell sorting, BIAcore analysis, and monoclonal antibody production. The Transgenic/Knockout Mouse Core will assist with vector design, transgenic mouse production, embryonic stem cell growth and transfection, breeding, and animal husbandry. Taken together, the exchange of ideas, reagents, and expertise, as well as the overall scientific synergy afforded by these multiple collaborations should allow this Program Project to continue to make important contributions to the science and practice of transfusion medicine.
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