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(申请人提供)：血小板是血液中循环的巨核细胞产生的亚细胞颗粒。作为圆盘，它们巡视血液-内皮界面，并对血管损伤做出反应，在强大的肌动蛋白细丝组装和细胞骨架重组的驱动下迅速改变形状。激活将它们转化为扩散形式，可以堵塞血管泄漏，并招募额外的血小板形成补丁。细丝蛋白A(flamin A，FLNA)是我们在1976年首次发现的一种在血小板中大量表达的多面性蛋白质，它可以将肌动蛋白细丝与von Willebrand因子受体的GP1b链连接起来。缺乏Flna的人类和小鼠会出现严重的发育异常，并伴有中风和出血。在小鼠体内产生了缺乏细丝素A(Flna)的血小板，并对这些血小板中可识别的许多缺陷进行了初步表征，揭示了血小板flna与基于ITAM的受体信号之间的密切关系。在AIMS中，我们将确定Flna与Syk的直接相互作用如何促进基于ITAM的血小板受体的信号传递。AIM 1将描述FLNA和Syk之间的绑定接口。目标2将确定Flna如何调节细胞中的Syk功能。目标3将确定这种相互作用的生理重要性。