Integrin Signaling in Hemostasis and Blood Diseases

整合素的激活受到细胞内信号的严格调控，整合素将信号分子定位到细胞粘附位点。这些关系与血液和血管细胞高度相关，其中整合素调节生长，分化，生存和功能。本项目的目的是表征血液和血管细胞中整合素信号传导的基本机制，以确定整合素信号传导的一般规则为共同目标。项目1将验证整合素alphaIIbbeta3利用一种涉及蛋白酪氨酸激酶和造血细胞特异性适配分子的新途径来促进粘附血小板和巨核细胞的细胞骨架重组的假设。特别的重点将放在鉴定蛋白质-蛋白质相互作用，启动和传播信号中继从alphaIIbbeta3到肌动蛋白。项目2将识别和表征抑制整合素激活的信号通路。将特别强调在基因筛选中发现的影响整合素激活的蛋白质，包括Ras gtpase、MAP激酶和PEA-15（一种死亡效应蛋白，含结构域蛋白）。项目3将验证整合素是复杂细胞内信号网络的组成部分的假设，其空间和时间调节的激活控制内皮细胞和单核细胞的迁移。它将确定这些网络如何调节局部整合素活性，以及整合素和机械力如何调节Rac、Cdc42、PAK和ERK激酶的局部激活来控制细胞迁移。项目4将通过确定Abl如何调节丝状足形成、细胞迁移和趋化性来研究Abl酪氨酸激酶和整合素信号传导之间的关系。它还将确定整合素如何刺激c-Abl的核输出，以及它们如何克服f -肌动蛋白对c-Abl活性的抑制。这些项目将由提供重组蛋白、细胞显微注射和成像能力以及行政协调的核心单位提供支持。该项目实现的协同效应将有助于更好地理解整合素信号，对止血、血管生物学和血液疾病具有重要意义。

Integrin activation is tightly regulated by intracellular signals, and integrins localize signaling molecules to sites of cell adhesion. These relationships are highly relevant to blood and vascular cells, where integrins regulate growth, differentiation, survival and function. The purpose of this Program Project is to characterize fundamental mechanisms of integrin signaling in blood and vascular cells, with the common goal of identifying general rules of integrin signaling. Project 1 will test the hypothesis that integrin alphaIIbbeta3 utilizes a novel pathway involving protein tyrosine kinases and hematopoietic cell- specific adapter molecules to promote cytoskeletal reorganization in adherent platelets and megakaryocytes. Particular emphasis will be placed on identifying protein-protein interactions that initiate and propagate signal relay form alphaIIbbeta3 to actin. Project 2 will identify and characterize signaling pathways that suppress integrin activation. Special emphasis will be placed on proteins identified in genetic screens to influence integrin activation, including Ras GTPases, MAP kinases, and PEA-15, a death effector, domain-containing protein. Project 3 will test the hypothesis that integrins are components of complex intracellular signaling networks whose spatially and temporally regulated activation governs endothelial cell and monocytic migration. It will determine how these networks regulate localized integrin activity, and how integrins and mechanical forces regulate localized activation of Rac, Cdc42, PAK and ERK kinases to control cell migration. Project 4 will examine relationships between Abl tyrosine kinases and integrin signaling by determining how Abl modulates filopodia formation, cell migration and chemotaxis. It will also determine how integrins stimulate the nuclear export of c-Abl and how they override the inhibition of c-Abl activity by F-actin. These projects will be supported by core units that provide recombinant proteins, cell microinjection and imaging capabilities and administrative coordination. The synergy achieved by this Program will lead to a better understanding of integrin signaling, with implications for hemostasis, vascular biology and blood diseases.