Collagens are the most thrombogenic macromolecular constituents of the blood vessel wall. Recent studies carried? out in several laboratories, including many by the applicant, have identified two distinct platelet surface collagen? receptors, the alpha2beta1 integrin and the glycoprotein (GP) VI complex. There is now agreement that the two receptors mediate platelet-collagen interactions via a two-step, two-site mechanism, as originally proposed by the applicant. However, the relative contributions of the two receptors to the overall process, and even the order of the two steps, is intensely debated. The recent development of the alpha2beta1 integrin-deficient mouse, the GP Vl-deficient mouse and appropriate assays and animal thrombosis models now affords the first unambiguous opportunity to address definitively the roles and contributions of the two receptors.
Aim 1 will employ cell biologic, biochemical, proteomic and in vivo approaches to define the separate, additive and synergistic contributions of the alpha2beta1 integrin and GPVI to platelet adhesion to collagen, collagen-induced platelet signaling and activation and the response to acute vascular injury.
This aim will also test two critical hypotheses regarding the """"""""activated phenotype"""""""" of the alpha2beta1 integrin using transgenic mice and platelets derived from them that express a mutant alpha2 integrin subunit that exhibits the """"""""activated phenotype"""""""". Accumulated epidemiologic evidence suggests that high level platelet surface expression of the alpha2beta1 integrin is an independent risk factor for myocardial infarction.
Aim 2 will use a mouse model of spontaneous myocardial infarction due to the transgenic over expression of a stable, active variant of? human PAI-1 (plasminogen activator inhibitor-1), an established risk factor for myocardial infarction in humans, to? experimentally define the role(s) of the alpha2beta1 integrin and GPVI alone and in combination in myocardial infarction.? Aim three extends to the human the role of platelet surface alpha2beta1 integrin expression as a risk factor for thrombotic and/or bleeding complications in patients undergoing invasive procedures in the newly established hybrid cardiac catheterization/cardiac surgery suite.
This aim will test the association of DNA polymorphisms linked to the level of alpha2beta1 integrin expression on platelets with clinical outcome in terms of bleeding or thrombotic manifestations and complications.
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