Cell Adhesion and Signaling in Blood and Vascular Cells

项目摘要 这个应用程序的主题是整合素，它们的调节以及它们对功能的贡献 血液和血管细胞的反应。Focus的整合素是αMβ2(Mac-1)、αIIbβ3、αVβ3和α5β1 但研究结果应该广泛适用于整合素。重点细胞是血管细胞--内皮细胞， 平滑肌细胞和周细胞--以及血细胞--白细胞和血小板。在血细胞上， 将考虑Mac-1在白细胞上的结合和GPIB在血小板上的结合。主要重点将是 放置在调节整合素功能的分子-kindlins、talin和paxlin-上，以确定它们如何 协同调节整合素的激活。这些细胞骨架蛋白的功能独立于 整合素激活活性也将被剖析。该方案由三个项目组成，每个项目都由 在他们的母校，克利夫兰诊所，华盛顿大学医院有成就的教职员工 克利夫兰和凯斯西部储备大学，位置都很近，都是由 机构间协议。爱德华·F·普洛博士将担任项目主任和项目负责人 1.本项目研究了kindlin-2调节整合素依赖和 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， 秦军博士将使用高分辨率的结构方法，结合突变和细胞 Talin调节整合素活化及其与Kindlins和Paxlin协同作用的研究 如此新颖的见解。他将决定Talin如何与肌动蛋白相互作用来控制组织 细胞骨架。医学博士Daniel Simon将领导项目3，并将考虑如何让整合素参与 白细胞上的MAC-1和血小板上的GPIB调节这些细胞参与炎症和 血栓形成。他的研究范围从基本的结构方法到小鼠的翻译研究，以及 人类提供关于他们对系统性狼疮的血栓和炎症贡献的见解 红斑狼疮。该计划得到了两个科学核心的支持，即蛋白质表达和纯化 (核心B)、动物模型和组织分析(核心C)以及行政核心(AC1)。一个 该计划的共同目标是继续并在项目和 他们的领导者解决了结构和生物机制，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对生物学的洞察 受整合素及其激活调节的重要反应，与血栓形成和 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.