Regulation of Integrin alphaIIbbetaIII Function bu Scavenger Receptor-B1

已知的调节血小板激活级联反应的新型血小板受体/配体的数量为 不断增长。最近的研究表明，清道夫受体B类，I型(SR-BI)在人和小鼠的血小板上都有表达。重要的是，血小板SR-BI表达水平的降低与患者的血小板聚集性增加有关。ApoE缺失背景的小鼠的总SR-B1缺乏会导致自发性心肌梗死和过早死亡。我们的初步研究表明，小鼠血小板SR-BI缺乏也与选择的生理激动剂引起的血小板活化和聚集显著增加有关。此外，我们最近发现了SR-BI的特异性配体，它们是体外整合蛋白活化和血小板聚集的有效抑制因子。 SR-BI和allbB33激活之间的联系机制是已知的。控制血小板的反应性被认为是预防急性心血管事件的关键，因此阐明SR-BI调节整合素激活的机制以及它是否在体内参与血栓事件是重要的。已经确定SR-BI可以在几种细胞类型中参与信令事件。此外，作为SR-BI的近亲，CD36在血小板中与Src家族的几种蛋白酪氨酸激酶相关，因此我们推测，SR-BI介导的血小板信号转导控制着血小板整合素allbpS的激活，从而控制血小板的聚集和血栓形成。这项建议的长期目标是确定 血小板SR-BI在血栓形成中的作用，以及其作用的确切分子和细胞机制。 目的：1.体外研究CIF SR-BI在整合素Allb(33)活化和血小板功能中的作用。目的II.明确SR-BI与血小板整合素allbft3活化之间的分子信号机制。目的III.我们寻求证据表明，在体内，血小板SR-BI在调节血小板活化和血栓形成中发挥重要作用。

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.