Support is requested to continue a program designed to advance understanding of molecular mechanisms of vascular disease and to promote development of new diagnostic, therapeutic, and preventive strategies through the collaborative efforts of a group of experienced scientists focused oh the unifying theme of cell adhesion. This interdisciplinary program will span disciplines of biochemistry, cell biology, ex-vivo and in vivo studies to assess the effects of blood flow on adhesion and signaling, and analysis of genetically-modified mice and zebrafish. In Project 1, Dr. Ginsberg will study the activation of integrins and resulting thrombus formation by platelets and arrest of leukocytes. Specific studies will address the activation of integrins in purified systems, the role of RIAM, the interactions and structure of integrin transmembrane domains, and the in vivo and ex vivo consequences of perturbing integrin activation in platelets and leukocytes. In Project 2, Dr.Shattil will continue to develop and utilize strategies to visualize interactions of proteins with platelet integrin alpha lIb beta 3 in living cells and he will analyze the signaling mechanisms of alpha V integrins in vivo in zebrafish. In Project 3, Dr. Ruggeri will build on advances in the structure of von Willebrand Factor (VWF) and platelet GPIb. Specifically, he will seek to better understand the biomechanical properties of the bonds between GPIb and VWF in flowing blood, the effects of thrombin on the GPlb/VWF interaction, and the biological role of a newly-discovered immunoglobulin modulator of thrombosis. Mouse Genetics Core Unit A, led by Dr. Petrich, will provide expertise, genomic constructs, genotyping, well characterized murine embryonic stem cells, and blastocyst injections for the purpose of genetic manipulation of mice. This core will be used to generate talin knock-ins that selectively perturb integrin activation and will provide conditional transgenic animals. Microfluidics Core Unit B, led by Dr. Groisman, a physicist, will develop and provide high throughput multichannel microfluidic flow systems to analyze platelet and leukocyte adhesion to conventional and patterned substrates under controlled shear stress. Administrative Core Unit C will continue to provide administrative support. Altogether, this interdisciplinary program will enable remarkable synergies amongst a group of accomplished investigators who will test new hypotheses and utilize and develop cutting edge methodologies to advance understanding of cell adhesion events in vascular biology and thrombosis.
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