The number of known novel platelet receptors/ligands that regulate the platelet activation cascade is growing. Recent studies demonstrated that scavengejr receptor class B, type I (SR-BI) is expressed on human and murine platelets. Importantly, reduced levels of platelet SR-BI expression are associated with increased platelet aggregation in patients. Total SR-Bl deficiency in mice on an apoE null background results in spontaneous myocardial infarction and premature death. Our preliminary studies showed that deficiency of SR-BI in murine platelets is also associated with remarkably increased platelet activation and aggregation in response to selected physiological agonists. In addition, we recently identified specific ligands for SR-BI that are potent inhibitors of integriri allbps activation andplatelet aggregation in vitro. Mechanisms linking SR-BI and allbB33 activation areniknown. Control of platelet reactivity is regarded as critical for prevention of acute cardiovascular events, thus the elucidation of mechanisms by which SR-BI may regulate integrin activation and whether it contributes to thrombotic events in vivo is important. It has been established that SR-BI may participate in signa ing events in several cell types. Moreover, CD36, a close relative of SR-BI, is associated in platelets wit i several protein-tyrosine kinases of theSrc family, Thus, we hypothesized that SR-BI-mediated signaling in platelets controls platelet integrin allbpS activation and, therefore, platelet aggregation and thrombosis. T ie long-term goal of this proposal is to determine the role platelet SR-BI is playing in thrombosis and to eluc date the exact molecular and cellular mechanisms of its contribution.
The specific Aims are:
Aim 1. To characterize the role cif SR-BI in integrin allb(33 activation andplatelet function in vitro.
Aim II. Toidentify the molecular signaling mechanisms linking SR-BI and activation of integrin allbft3 in platelets.
Aim III. Wewillseek to obtain evidence that platelet SR-BIplays a significant role in the regulation of platelet activation and thrombosis in vivo.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL073311-10
Application #
8468199
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
10
Fiscal Year
2013
Total Cost
$298,503
Indirect Cost
$95,660
Name
Cleveland Clinic Lerner
Department
Type
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
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