Regulation of Integrin alphaIIbbetaIII Function bu Scavenger Receptor-B1

已知的调节血小板活化级联反应的新型血小板受体/配体的数量是 增长.最近的研究表明，清道夫受体B类，I型（SR-BI）表达于人和鼠血小板上。重要的是，血小板SR-BI表达水平降低与患者血小板聚集增加相关。在apoE无效背景下的小鼠中总SR-Bl缺乏导致自发性心肌梗死和过早死亡。我们的初步研究表明，小鼠血小板中SR-BI的缺乏也与血小板活化和聚集的显著增加有关，血小板活化和聚集是对所选择的生理激动剂的反应。此外，我们最近鉴定了SR-BI的特异性配体，它们是体外整合素allbps激活和血小板聚集的有效抑制剂。 SR-BI和allbB 33激活的联系机制尚不清楚。血小板反应性的控制被认为是预防急性心血管事件的关键，因此阐明SR-BI可调节整合素活化的机制以及其是否有助于体内血栓形成事件是重要的。已经确定SR-BI可以参与几种细胞类型中的信号事件。此外，CD 36是SR-BI的近亲，在血小板中与Src家族的几种蛋白酪氨酸激酶相关。因此，我们假设血小板中SR-BI介导的信号传导控制血小板整合素α 1 β 3活化，从而控制血小板聚集和血栓形成。该提案的长期目标是确定 血小板SR-BI在血栓形成中的作用，并阐明其作用的确切分子和细胞机制。 目的：1.探讨SR-BI在体外对整合素α 1b β_3活化和血小板功能的影响。Aim II.研究血小板整合素allbft 3活化与SR-BI的关系。Aim III.我们将寻求证据证明血小板SR-BI在体内血小板活化和血栓形成的调节中发挥重要作用。

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.