Cell Adhesion and Signaling in Blood and Vascular Cells

项目摘要 本申请的主题是整合素，它们的调节和它们对功能性免疫应答的贡献。 血液和血管细胞的反应。病灶的整合素为αMβ2（Mac-1）、αIIbβ3、αVβ3和α5β1 但研究结果应适用于广泛的整合素。重点细胞是血管细胞-内皮细胞， 平滑肌细胞和周细胞-和血细胞-白细胞和血小板。在血细胞上， 将考虑白细胞上Mac-1和血小板上GPIb的结合。重点将是 放置在调节整合素功能的分子上--kindlin，talin和paxillin--以确定它们如何 协同调节整合素活化。这些细胞骨架蛋白的功能不依赖于 还将剖析整联蛋白活化活性。该方案包括三个项目，每个项目由 一个有成就的教员在他们的家乡机构，克利夫兰诊所，大学医院， 克利夫兰和凯斯西储大学，都位于附近，并由 机构间协议。Edward F.博士Plow博士将担任项目总监并领导项目 1.该项目涉及kindlin-2调节整合素依赖性和 血管细胞的独立反应。分子，细胞和独特的小鼠模型都带来了 以确定kindlin-2如何作为血管细胞反应的主要调节因子。在项目2中， 博士秦军将使用高分辨率结构方法结合诱变和细胞 研究确定talin如何调节整合素活化，并与kindlin和桩蛋白合作， 如此新颖的见解。他将确定塔林如何与肌动蛋白相互作用，以控制 细胞骨架丹尼尔西蒙博士，医学博士我将领导项目3，并将考虑如何参与整合素 白细胞上的Mac-1和血小板上的GPIb调节这些细胞参与炎症， 血栓形成他的研究范围从基本的结构方法到小鼠的转化研究， 人类提供深入了解他们的血栓和炎症的贡献，系统性狼疮 红斑该计划由两个科学核心支持，蛋白质表达和纯化 (Core B）和动物模型和组织分析（核心C）以及管理核心（AC 1）。一 该计划的共同目标是继续和创造新的项目之间的合作， 他们的领导人解决结构和生物机制，调节整合素的功能， 血液和血管细胞。从这些研究中获得的信息将提供生物学上的见解， 与血栓形成相关的由整合素及其活化调节的重要反应， 心血管疾病

Project Summary This application has as its theme the integrins, their regulation and their contribution to the functional responses of blood and vascular cells. The integrins of focus are αMβ2 (Mac-1), αIIbβ3, αVβ3, and α5β1 but findings should apply to broadly integrins. The cells of emphasis are vascular cells- endothelial cells, smooth muscle cells and pericytes- and blood cells- leukocytes and platelets. On the blood cells, the conjugation of Mac-1 on leukocytes and GPIb on platelets will be considered. Major emphasis will be placed on the molecules that regulate integrin function- kindlins, talin and paxillin- to determine how they collaborate to regulate integrin activation. The function of these cytoskeletal proteins independent of integrin activating activity will also be dissected. The Program consists of three projects, each directed by an accomplished faculty member at their home institutions, Cleveland Clinic, University Hospitals of Cleveland and Case Western Reserve University which are all closely located and governed by interinstitutional agreements. Dr. Edward F. Plow, Ph.D. will serve as Program Director and lead Project 1. This project deals with the mechanisms by which kindlin-2 regulates both integrin-dependent and independent responses of blood vessel cells. Molecular, cellular and unique mouse models are all brought to bear to determine how kindlin-2 serves as a master regulator of vascular cell responses. In Project 2, Dr. Jun Qin will use high resolution structural approaches in combination with mutagenesis and cellular studies to determine how talin regulate integrin activation and cooperates with kindlins and paxillin to gain such novel insights. He will determine how talin interacts with actin to control organization of the cytoskeleton. Dr. Daniel Simon, M.D. will lead Project 3 and will consider how engagement of integrin Mac-1 on leukocytes and GPIb on platelets regulates the participation of these cells in inflammation and thrombosis. His studies range from basic structural approaches to translational studies in mice and to humans to provide insights into their thrombotic and inflammatory contributions to systemic lupus erythematosus. The Program is supported by two Scientific Cores, Protein Expression and Purification (Core B), and Animal Models and Tissue Analysis (Core C) as well as by an Administrative Core (AC1). A common objective of the Program is to continue and create new collaborations among the Projects and their Leaders to resolve the structural and biological mechanisms that regulate the functions of integrins in blood and vascular cells. The information derived from these studies will provide insights into biologically important responses regulated by integrins and their activation that are relevant to thrombosis and cardiovascular diseases.