Mechanisms of Microvascular Control and Coordination in Health and Disease

描述（由申请人提供）：这是一个修订后的新计划项目申请，来自一个由3个项目和3个核心组成的经验丰富的研究人员互动组。本PPG的总体主题是了解小动脉如何通过细胞整合素和细胞外基质（ECM）蛋白之间的相互作用进行调节，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见解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，这将大大促进我们对微血管控制这一范式的理解。该PPG的中心前提是健康和疾病中的微血管控制受ECM的性质以及ECM与微血管壁细胞上的整合素的相互作用的影响。项目1将检查血管活性介质影响整合素-ECM粘附的能力，并确定粘附如何与微血管平滑肌细胞（mVSMC）收缩和小动脉直径控制协调。项目2将检查ECM蛋白通过整合素发出信号并调节Mvsmc膜Ca 2+和K+电导以控制血管紧张素的能力。项目3研究了一个独特的假设，即在炎症过程中，白细胞迁移导致ECM降解，产生整合素结合信号，损害对小动脉的控制。核心A将为项目编制补助金提供行政支助。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技术。这些项目将共同形成一个微血管调节的综合观点，使用模型系统，包括新鲜分离的mVSMC，分离的小动脉和微血管网络制剂。一个多学科的技术方法，从原子力显微镜，荧光显微镜，电生理学和分子技术，将允许一个全面和系统的探索的概念。(End摘要）

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)