Molecular Mechanisms of Arterigenesis

描述(申请人提供)：动脉形成是在发育过程中或成人循环中形成新的动脉血管的过程。在发育过程中，它需要形成具有动脉特征的新的内皮血管结构，其定义由关键标记物如肾上腺素82和神经毛细蛋白1的表达所定义，然后获得中膜和外膜。在成人循环中，通过扩张原有的动脉血管结构或从头开始形成新的动脉。血管内皮生长因子及其受体VEGFR2或关键的细胞内信号介质缺失会导致动脉血管发育失败。动脉生成缺陷在其他情况下也会被注意到，包括eNOS的缺失，或者在糖尿病和高胆固醇血症等疾病状态下，这种缺陷极大地导致了与这些疾病相关的发病率和死亡率。然而，人们对整个过程知之甚少，目前还没有成功的方法来处理其在临床环境中的缺陷。了解动脉形成的分子机制将有助于我们了解主要心血管疾病的病理生物学，并有助于开发新的治疗方法来对抗这些疾病。在这篇PPG中，我们提出了一种全面的方法来研究动脉形成的分子基础，并为这一领域的治疗进展开发新的智力框架。为此，我们将研究一条似乎对动脉形成至关重要的新的信号通路(项目1)，研究一氧化氮和细胞外基质的作用(项目2)，评估mTOR在平衡各种动脉形成信号输入中的中心作用(项目3)，并确定剪应力和其他机械因素在启动动脉形成中的作用。

DESCRIPTION (provided by applicant): Arteriogenesis is the process of formation of new arterial blood vessels during development or in the adult circulation. In development it entails formation of new endothelial vascular structures with arterial identity as defined by expression of key markers such ephrin 82 and neuropilin 1 followed by acquisition of the media and adventitia. In the adult circulation new arteries arise either by expansion of the pre-existing arterial vascular structures or de novo. Deletion of VEGF, its receptor VEGFR2 or key intracellular signaling mediators results in failure of arterial vasculature development. Defective arteriogenesis is noted in other setting including deletion of eNOS or in disease states such as diabetes and hypercholesterolemia and this failure contributes greatly to morbidity and mortality associated with these diseases. Nevertheless, the entire process is little understood and there are no currently successful approaches to deal with its defects in clinical settings. Understanding of molecular mechanism regulating arteriogenesis would be of great benefit to our understanding of pathobiology of major cardiovascular illnesses and to the development of new therapeutic approaches to combat them. In this PPG we propose a comprehensive approach to investigate the molecular basis of arteriogenesis and to develop new intellectual framework for therapeutic advances in this field. To this end, we will investigate a novel signaling pathway that seems to be critical to arteriogenesis (Project 1), study contributions of nitric oxide and the extracellular matrix (Project 2), evaluate the central role of mTOR in balancing various arteriogenic signaling inputs (Project 3) and determine the role of shear stress and other mechanical factors in initiating arteriogenesis in ad