Filamin A - Syk Interactions Modulate Platelet ITAM-based Signaling

性状（由申请方提供）：血小板是由血液中循环的巨核细胞产生的亚细胞颗粒。作为圆盘，它们巡逻血液-内皮界面，并且响应于血管损伤，在由强大的肌动蛋白丝组装和细胞骨架重组驱动的反应中迅速改变形状。激活后，它们会转化为扩散形式，可以堵塞血管渗漏，并招募更多的血小板形成补丁。细丝蛋白A（FLNa），首先由我们在1976年发现，是一种多方面的蛋白质，在血小板中大量表达，已知它交联肌动蛋白丝并将其连接到血管性血友病因子受体的GP 1b链。缺乏FLNa的人类和小鼠具有严重的发育异常，伴有中风和出血。在小鼠中产生缺乏细丝蛋白A（FLNa）的血小板以及在这些血小板中可识别的许多缺陷的初步表征揭示了血小板FLNa与基于ITAM的受体信号传导之间的密切关系。在目标中，我们将确定FLNa与Syk的直接相互作用如何促进血小板ITAM受体的信号传导。目的1：研究FLNa与Syk的结合界面。目的2将确定FLNa如何调节细胞中的Syk功能。目的3将确定这种相互作用的生理重要性。

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.