Mechanisms of Microvascular Control and Coordination in Health and Disease

描述(由申请人提供)：这是一个由3个项目和3个核心组成的由经验丰富的研究人员组成的互动小组提出的修订后的新项目项目申请。PPG的总体主题是了解细胞整合素和细胞外基质(ECM)蛋白之间的相互作用如何调节小动脉，以及这些相互作用如何受到血管疾病的干扰。在过去的12年里，项目研究人员发表了大部分早期工作，确立了整合素在微血管控制中的关键作用。我们的研究团队最近的洞察力已经确定了关键的整合素和ECM蛋白，为该领域的重大突破奠定了基础，这将极大地促进我们对这一微血管控制范式的理解。这种PPG的一个中心前提是，健康和疾病中的微血管控制受到ECM的性质以及ECM与微血管壁细胞上的整合素相互作用的影响。项目1将研究血管活性介质影响整合素-ECM黏附的能力，并确定黏附如何与微血管平滑肌细胞(MVSMC)收缩和微动脉直径控制相协调。项目2将研究细胞外基质蛋白通过整合素发出信号的能力，并调节Mvsmc膜上钙离子和钾离子的电导来控制血管舒缩张力。项目3检验了一个独特的假设，即在炎症期间，迁移的白细胞会导致细胞外基质降解，从而产生整合素结合信号，从而削弱对小动脉的控制。核心A将为PPG提供行政支持。对于所有项目，核心B将提供成像技术/支持，核心C将提供分子和细胞级别的技术。总而言之，这些项目将使用包括新鲜分离的mVSMC、分离的小动脉和微血管网络制剂的模型系统来形成微血管调节的综合视图。从原子力显微镜、荧光显微镜、电生理学和分子技术在内的一系列多学科的技术方法将允许对概念进行全面和系统的探索。(摘要结束)

DESCRIPTION (provided by applicant): This is a revised new Program Project application from an interactive group of experienced investigators consisting of 3 projects and 3 cores. The overall theme of this PPG is to understand how arterioles are regulated by interactions between cell integrins and extracellular matrix (ECM) proteins and how these interactions are disturbed by vascular disease. Over the last 12 years, program investigators published most of the early work establishing a key role for integrins in microvascular control. Recent insights by our investigative team have identified key integrins and ECM proteins setting the stage for major breakthroughs in this field that will significantly advance our understanding of this paradigm for microvascular control. A central premise of this PPG is that microvascular control in health and disease is influenced by properties of the ECM and ECM interactions with integrins on cells of the microvascular wall. Project 1 will examine the ability of vasoactive mediators to influence integrin-ECM adhesion and determine how adhesion is coordinated with microvascular smooth muscle cell (mVSMC) contraction and control of arteriole diameter. Project 2 will examine the ability of ECM proteins to signal through integrins and modulate Mvsmc membrane conductance of Ca2+ and K+ to control vasomotor tone. Project 3 examines a unique hypothesis that during inflammation emigrating leukocytes cause ECM degradation that generates integrin-binding signals that impair control of arterioles. Core A will provide administrative support for the PPG. For all projects, Cores B will provide imaging technology/support and Core C will provide for molecular and cell level technologies. Together, the projects will shape an integrated view of microvascular regulation using model systems that include freshly isolated mVSMC, isolated arterioles and microvascular network preparations. A multidisciplinary array of technical approaches ranging from atomic force microscopy, fluorescence microscopy, electrophysiology and molecular techniques will allow a comprehensive and systematic exploration of concepts. (End of Abstract)