Filamin A - Syk Interactions Modulate Platelet ITAM-based Signaling

Filamin A - Syk 相互作用调节血小板基于 ITAM 的信号传导

• 批准号: 8306163
• 负责人: John H Hartwig
• 金额: $ 40.7万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-15 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8306163
• 关键词: Address; Adoptive Transfer; Binding; Binding Proteins; Binding Sites; Blood; Blood Platelets; Blood Vessels; Cells; Cessation of life; Complex; Computer Simulation; Cytoskeletal Modeling; Defect; Development; Disease; Dissection; Dominant-Negative Mutation; Event; F-Actin; Generations; Goals; Hemorrhage; Human; ITAM; In Vitro; Knowledge; Laboratories; Lead; Ligation; Link; Literature; Maps; Marrow; Megakaryocytes; Microfilaments; Modeling; Modification; Mus; Myocardial Infarction; Pathway interactions; Patients; Pharmaceutical Preparations; Physiological; Platelet Activation; Platelet aggregation; Prevention; Proteins; Reaction; Receptor Signaling; Recording of previous events; Recruitment Activity; Scheme; Shapes; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Stem cells; Stroke; base; crosslink; filamin; in vivo; insight; interest; mutant; particle; receptor; response; restoration; von Willebrand factor receptor

DESCRIPTION (provided by applicant): Platelets are subcellular particles produced by megakaryocytes that circulate in blood. As discs, they patrol the blood-endothelial interface, and in response to vascular damage, rapidly change shape, in a reaction driven by robust actin filament assembly and cytoskeletal reorganization. Activation converts them into spread forms that can plug vascular leaks and recruit additional platelets to form a patch. Filamin A (FLNa), first identified by us in 1976, is a multifaceted protein abundantly expressed in platelets where it is known to crosslink actin filaments and link them to the GP1b chain of the von Willebrand factor receptor. Humans and mice lacking FLNa have severe developmental abnormalities, accompanied by stroke and hemorrhage. The generation of platelets that lack filamin A (FLNa) in mice and the initial characterization of the many defects identifiable in these platelets, have revealed an intimate relationship between platelet FLNa and ITAM-based receptor signaling. In the aims, we will determine how a direct interaction of FLNa with Syk promotes signaling from platelet ITAM-based receptors. Aim 1 will delineate the binding interface between FLNa and Syk. Aim 2 will determine how FLNa modulates Syk function in cells. Aim 3 will establish the physiological importance of this interaction.

描述（由申请人提供）：血小板是由血液循环的巨核细胞产生的亚细胞颗粒。作为椎间盘，它们会在血液内皮界面巡逻，并响应血管损伤，迅速改变形状，这是由稳健的肌动蛋白丝组件和细胞骨架重组驱动的反应。激活将它们转换为传播形式，可以堵塞血管泄漏并募集其他血小板形成补丁。 Filamin A（FLNA），由我们于1976年首次鉴定出来，是一种多面蛋白，在血小板中大量表达，已知可以交叉肌动蛋白丝并将其链接到von Willebrand因子受体的GP1B链。缺乏FLNA的人和小鼠具有严重的发育异常，并伴有中风和出血。在小鼠中缺乏丝蛋白A（FLNA）的血小板的产生以及在这些血小板中可识别的许多缺陷的初始表征，揭示了血小板FLNA与基于ITAM的受体信号传导之间的紧密关系。在目的中，我们将确定FLNA与SYK的直接相互作用如何促进基于血小板ITAM受体的信号传导。 AIM 1将描绘FLNA和SYK之间的结合界面。 AIM 2将确定FLNA如何调节细胞中的SYK功能。 AIM 3将确定这种相互作用的生理重要性。