MECHANISMS OF CARDIOVASCULAR REACTION TO INJURY

描述（由申请人提供）：本申请代表“心血管损伤反应机制”计划项目的竞争性更新。 该项目已进入第48个年头，为我们理解血管内膜和动脉粥样硬化斑块的发展做出了重要贡献，包括提出了动脉粥样硬化发病机制的"损伤反应"和"单克隆"假说。 目前的应用包括对心脏对损伤的反应的新强调，同时也继续在血管生物学方面开展工作。 一个中心主题是，这两种不同类型的肌肉组织在对损伤的反应中表现出许多相似之处。 我们的目标是了解细胞死亡的途径，定义受损组织的正常适应性和修复性反应，并开发控制这些过程的分子策略。 项目1将专注于控制骨骼肌细胞移植到梗死心脏后的增殖，并确定调节梗死修复的关键分子和细胞分化途径。 项目2将确定伤口修复中的细胞在多大程度上来源于预先存在的局部来源、骨髓或非骨髓细胞的转分化。 该项目还将继续研究PDGF系统在伤口愈合中的作用。 项目3建立在动脉表达比静脉高许多倍的RGS蛋白水平的观察的基础上，测试RGS蛋白是高血压重塑和侧支循环形成中血管肥大的关键介质的假设。 这3个项目由一个动物/组织核心和一个行政核心支持，前者协助小鼠饲养和组织学。我们希望这些研究的信息不仅能教会我们如何在受伤的心脏中更好地生长新的肌肉，还能教会我们如何创造一个更好的“土壤”来生长新的肌肉。

DESCRIPTION (provided by applicant): This application represents a competing renewal of the Program Project "Mechanisms of Cardiovascular Reaction to Injury". Now in its 48th year, this Program has made important contributions to our understanding of development of the vascular intima and the atherosclerotic plaque, including generating the "Response to Injury" and the "Monoclonal" hypotheses for the pathogenesis of atherosclerosis. The current application includes a new emphasis on the heart's response to injury, while continuing work in vascular biology as well. A central theme is that these two different types of muscle tissue will show many similarities in their reactions to injury. Our aims are to understand pathways to cell death, define normal adaptive and reparative responses of the injured tissues, and to develop molecular strategies to control these processes. Project 1 will focus on controlling proliferation of skeletal muscle cells after grafting into the infarcted heart, and defining the key molecules and cell differentiation pathways that regulate infarct repair. Project 2 will determine the extent to which cells in wound repair are derived from preexisting local sources, the bone marrow, or transdifferentiation of non-marrow cells. This project will also continue its studies of the role of the PDGF system in wound healing. Project 3 builds on the observation that arteries express many-fold higher levels of RGS proteins that do veins, testing the hypothesis that RGS proteins are critical mediators of vascular hypertrophy in hypertensive remodeling and formation of collateral circulation. These 3 projects are supported by an Animal/Tissue Core to assist in mouse husbandry and histology and by an Administrative Core. We expect that information from these studies will teach us, not only how to better grow new muscle in the injured heart, but also how to create a better "soil" in which new muscle can be grown.