The human platelet plasma membrane contains several hundred different proteins that control crucial functions,? including adhesion to extracellular matrix, signal transduction, platelet aggregation, and clot retraction. Central to? the ability of platelets to adhere to each other and to extracellular matrix is an abundant supply of cell surface? adhesion molecules, including members of the integrin family, that exist in varying states of activation. These cell? adhesion receptors, in turn, transmit signals into, and respond to signals from, the cell interior. The molecular? details of the signaling pathways that regulate platelet activation and adhesion, however, remain incompletely? understood. The goal of this project, therefore, is to examine four interrelated aspects of the molecular mechanisms? underlying platelet activation and adhesion.
Specific Aim 1 seeks to understand the molecular mechanism by? which antibodies to platelet membrane glycoprotein (GP) VI result in the surgical removal of this important? adhesion and signaling complex from the platelet surface, rendering platelets unresponsive to the extracellular? matrix component, collagen, and less likely to participate in thrombus formation. It is hoped that these studies may? enable rational design of future GPVI-specific therapeutics for the treatment of myocardial infarction and stroke.? Specific Aim 2 proposes to test a recently-proposed and attractive hypothesis that specific amino acids within the? membrane proximal beta-terminal domain of the integrin beta3 subunit control access of macromolecular ligands like? fibrinogen and von Willebrand factor to ligand contact sites within the integrin head domain. These studies should? provide important insights into how subtle allosteric changes within the extracellular domain might enable? transformation of integrins from a low- to high-affinity state.
Specific Aim 3 proposes to explore the hypothesis? that PECAM-1 functions as an inhibitory receptor by sequestering the protein-tyrosine phosphatase, SHP-2, away? from proteins that regulate the activation of Src family kinases. These studies will shed important new light on the? mechanism by which PECAM-1, and perhaps other SHP-2 binding proteins, function to modulate cellular? activation. Finally, Specific Aim 4 is a hypothesis-generating, translational research aim that seeks to determine? whether PECAM-1 expression varies in the human population, and whether variable PECAM-1 expression might? predispose individuals to arterial thrombosis or hemorrhage. These studies have the potential to add PECAM-1 to? the growing list of cell adhesion and signaling receptors whose expression is linked to bleeding and clotting? disorders in humans, and may thereby improve our ability to diagnose, treat, and prevent clinical thrombosis in? humans. Together, these studies represent a coordinated line of investigation designed to advance our? understanding of platelet physiology and lead to improvements in transfusion therapy, platelet storage, and? management of platelet functional and immunological disorders.
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