Cell Adhesion and Signaling in Blood and Vascular Cells

血液和血管细胞中的细胞粘附和信号传导

• 批准号: 10471908
• 负责人: JUN QIN
• 金额: $ 243.06万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10471908
• 关键词: Actins; Address; Agreement; Amaze; Animal Model; Atherosclerosis; Binding; Biological; Biological Process; Biology; Blood; Blood Cells; Blood Circulation; Blood Platelets; Blood Vessels; Cardiovascular Diseases; Cardiovascular Pathology; Cardiovascular Physiology; Cardiovascular system; Cell Adhesion; Cell Surface Receptors; Cell Wall; Cells; Cellular biology; Clinic; Collaborations; Complex; Core Protein; Cytoplasmic Tail; Cytoskeletal Proteins; Cytoskeleton; Disease; Doctor of Medicine; Doctor of Philosophy; Endothelial Cells; Event; Faculty; Future; Gene Expression; Goals; Home; Human; Inflammation; Inflammatory; Innate Immune System; Institution; Integrin beta Chains; Integrins; International; Investigation; Knowledge; Lead; Leukocytes; Ligand Binding; Ligands; Ligation; Macrophage-1 Antigen; Mediating; Membrane Proteins; Molecular; Mus; Mutagenesis; Pathologic; Pathology; Pericytes; Physicians; Physiological; Process; PubMed; Publications; Regulation; Research Personnel; Resolution; Role; Running; Scientist; Signal Transduction; Smooth Muscle Myocytes; Structural Biologist; Structure; Systemic Lupus Erythematosus; Talin; Thrombosis; Universities; University Hospitals; Ursidae Family; Vascular Endothelial Cell; Venous Thrombosis; angiogenesis; animal tissue; insight; member; mouse model; new therapeutic target; novel; novel diagnostics; paxillin; programs; protein expression; protein purification; response; thrombotic; translational study; wound healing

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.

项目概要 该应用程序的主题是整合素、它们的调节及其对功能的贡献 血液和血管细胞的反应。焦点整合素是 αMβ2 (Mac-1)、αIIbβ3、αVβ3 和 α5β1 但研究结果应该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-以及血细胞-白细胞和血小板。在血细胞上， 将考虑将 Mac-1 与白细胞结合，将 GPIb 与血小板结合。主要重点将是 将其置于调节整合素功能的分子（kindlins、talin 和 paxillin）上，以确定它们如何 合作调节整合素激活。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。该计划由三个项目组成，每个项目由 一位在其所在机构、克利夫兰诊所、大学医院等有成就的教员 克利夫兰大学和凯斯西储大学都位于很近的地方并受其管辖 机构间协议。爱德华·普洛博士，博士将担任项目总监并领导项目 1. 该项目研究 kindlin-2 调节整合素依赖和整合素依赖的机制 血管细胞的独立反应。分子、细胞、独特的小鼠模型全部带来 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结构方法结合诱变和细胞 研究确定talin如何调节整合素激活并与kindlins和paxillin合作以获得 如此新颖的见解。他将确定talin如何与肌动蛋白相互作用来控制肌动蛋白的组织 细胞骨架。 Daniel Simon 医学博士将领导项目 3，并将考虑整合素如何参与 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结构方法到小鼠转化研究，以及 人类深入了解血栓和炎症对系统性狼疮的影响 红斑狼疮。该计划由两个科学核心支持：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项目之间建立新的合作 他们的领导人解决了调节整合素功能的结构和生物学机制 血液和血管细胞。从这些研究中获得的信息将为生物学提供见解 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。