Molecular Mechanisms of Arterigenesis

本项目的总体目标是了解调节细胞凋亡的分子机制。 动脉生成可作为血管闭塞性心血管疾病的潜在治疗方法 包括冠状动脉疾病、外周动脉疾病和脑血管疾病 疾病我们组建了一支多学科的团队，由具有不同专长的 背景（心脏病学，细胞生物学，生物力学工程，药理学）研究 导致动脉血管系统发育和生长的关键分子事件。深入 对这些机制的理解可以被用于开发新的 这是一组重要的心血管疾病的治疗方式。我们的研究 将定义导致动脉血管生长的关键事件，并将导致 新疗法 PPG的目标是： 目标1。阐明ERK信号传导如何控制动脉生成（项目1）。 目标二。揭示miR 17-92簇在控制动脉生成中的作用及其 调节和与ERK信号的相互作用（项目2 目标3。确定流体剪切应力和细胞外基质的变化如何激活 ERK和其他信号通路介导动脉生成，并确定限制 在疾病中损害动脉生成的点（项目3）。 与公共卫生的相关性：冠状动脉疾病和外周动脉疾病是主要的 发达国家的疾病和死亡原因。不良的动脉生成是一个关键的决定因素， 这些疾病和心肌梗死后患者的恢复。本申请建议 阐明控制血流依赖性血管重塑的信号网络， 改善动脉生成的新方向。这些研究包括测试是否激活 动脉生成信号通路改善疾病模型中的动脉生成。他们有 有可能确定新的目标和新的治疗试剂，以及实现更深层次的 对基础生物学的理解将成为未来研究的基础。

The overall goal of this Program Project is to understand molecular mechanisms regulating arteriogenesis that may be exploited as potential treatments for vasoocclusive cardiovascular diseases including coronary artery disease, peripheral arterial disease and cerebrovascular disease. We have assembled a multidisciplinary team of highly accomplished PIs with diverse backgrounds (cardiology, cell biology, biomechanical engineering, pharmacology) to investigate key molecular events that lead to development and growth of arterial vasculature. The in-depth understanding of these mechanisms can then be parlayed into development of novel therapeutic modalities for this important group of cardiovascular diseases. Together, our studies will define the key events leading to arterial vessel growth and will lead to the development of new therapies. PPG Aims are: Aim 1. Elucidate how ERK signaling controls arteriogenesis (Project 1). Aim 2. Unravel the role of the miR 17-92 cluster in controlling arteriogenesis and its regulation and interaction with ERK signaling (Project 2 Aim 3. Determine how fluid shear stress and changes in the extracellular matrix activate ERKs and other signaling pathways that mediate arteriogenesis, and identify restriction points that impair arteriogenesis in disease (Project 3). Relevance to Public Health: Coronary artery disease and peripheral artery disease are major causes of illness and death in developed nations. Poor arteriogenesis is a critical determinant of these diseases and in patients’ recovery after myocardial infarction. This application proposes to elucidate the signaling network that governs flow-dependent vessel remodeling and test two new directions for improving arteriogenesis. These studies include testing whether activating an arteriogenic signaling pathway improves arteriogenesis in disease models. They have the potential to identify new targets and new reagents for therapy, as well as to achieve a deeper understanding of the fundamental biology that will form the basis for future studies.