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 on the unifying theme of cell adhesion. These studies will span analysis of biochemistry, fine structure at atomic level detail, ex-vivo studies to analyze the effects of blood flow on adhesion and signaling, hematopoiesis, and analysis of genetically modified mice. Dr. Ginsberg will study talin, a cytoskeletal protein, and its interactions with beta3 integrins and the succeeding consequences for activation of integrin alpha IIb beta 3 (GPIIb-IIIa) and resulting platelet aggregation and thrombosis. Specific studies will address the regulation of talin binding to the integrin, the mechanism by which talin induces activation of integrin alpha IIb beta 3, and the in vivo and ex vivo consequences of perturbing that interaction. Dr. Kaushansky will study the developmental biology of adhesive signaling in the platelet lineage. A major focus will be the intersection between adhesive and thrombopoietin signaling in hematopoietic stem cells, megakaryocytes and platelets and the consequences of this intersection for platelet thrombus formation. Dr.Shattil will continue to develop and utilize strategies to manipulate the expression and study the function of integrin alpha IIb beta 3 and other genes in mouse megakaryocytes and platelets, both ex vivo and in vivo. A central focus will be the mechanisms and consequences of the association of c-Src and Protein Kinase C with alpha IIb beta 3 in platelets and megakaryocytes. Dr. Ruggeri will build on recent advances in the structure of von Willebrand Factor (vWF) and platelet GPIb. Specific foci will be on the biomechanical properties of the bonds between GPIb and vWF in flowing blood and intracellular signaling pathways that connect this interaction to platelet aggregation. A mouse genetics core, directed by Dr. Marth, will provide expertise, genomic constructs, genotyping, well characterized murine embryonic stem cells, and blastocyst injections for the purpose of genetic manipulation of mice and ES cells. This core will be used to generate integrin beta3 knock ins that selectively perturb interactions with Src kinases or with talin and talin knock ins that disrupt integrin activation, phosphorylation, or phosphoinositide binding. An administrative core will continue to provide administrative support.
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