Integrin Signaling in Hemostasis and Blood Diseases

整合素活化受细胞内信号的严格调节，并且整合素将信号分子定位于细胞粘附位点。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，存活和功能。该项目的目的是描述整合素信号在血液和血管细胞中的基本机制，共同目标是确定整合素信号的一般规则。项目1将检验整合素α IIb β 3利用涉及蛋白酪氨酸激酶和造血细胞特异性衔接分子的新途径促进粘附血小板和巨核细胞中细胞骨架重组的假设。特别强调将放在确定蛋白质-蛋白质的相互作用，启动和传播信号中继从α IIb β 3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。将特别强调在遗传筛选中鉴定的影响整合素活化的蛋白质，包括Ras GTP酶，MAP激酶和PEA-15，一种死亡效应子，含结构域的蛋白质。项目3将测试整合素是复杂的细胞内信号网络的组成部分，其空间和时间调节的激活控制内皮细胞和单核细胞迁移的假设。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，Cdc 42，PAK和ERK激酶的局部激活以控制细胞迁移。项目4将通过确定Abl如何调节丝状伪足形成、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。这些项目将得到提供重组蛋白、细胞显微注射和成像能力以及行政协调的核心单位的支持。该计划实现的协同作用将导致更好地了解整合素信号传导，对止血，血管生物学和血液疾病的影响。

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.