? This is a revised competitive renewal application for years 16-20 of Program Project Grant HL-44612, which provides support for a coordinated, multi-disciplinary investigation of molecular and cellular mechanisms important to the field of transfusion medicine - a discipline that, despite its obvious importance to the nation's health, has historically been underrepresented in both training and research resources. Our application reflects ongoing, close collaborative ties that have existed amongst the Project Leaders for more than a decade, and who remain committed to interrelated research projects centered around the biology of blood and vascular cells. In the first Project, Peter and Debra Newman propose four interrelated aims that seek to further our understanding of the cell surface receptors and associated signaling pathways that regulate platelet activation and adhesion. In the second Project, Dick Aster proposes to continue his investigation of pre-existing, """"""""naturally-occurring"""""""" antibodies that cause acute platelet destruction in patients exposed to abciximab or ligand-mimetic GPIIb/IIIa inhibitors, and ? may have important implications for other immune disorders. The third Project, led by Cheryl Hillery, seeks to define how blood coagulation pathways contribute to sickle cell-induced organ damage, and to explore potential therapies that limit both acute episodes of vaso-occlusion and the accompanying chronic organ damage. The fourth Project, led by Bob Montgomery continues to explore the structural requirements for VWF biosynthesis that lay the foundation for an entirely novel replacement therapy approach for the treatment of patients with severe hemophilia A. The Shared Instrumentation Core will continue to provide centralized instrumentation and expertise for DNA sequence analysis, peptide synthesis, microscopy/digital image analysis, histology, 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 overall scientific synergy of ideas, reagents and expertise afforded by these multiple collaborations should enable this Program Project in Transfusion Medicine Research, to advance our understanding of the biology of blood and vascular cells, and to apply findings made toward treating blood diseases and enhancing the effectiveness of transfusion therapy.
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