Molecular Mechanisms of Arterigenesis

描述（由申请人提供）：动脉生成是在发育期间或在成人循环中形成新动脉血管的过程。在发育过程中，它需要形成具有动脉特性的新内皮血管结构，如通过关键标志物如肝配蛋白82和神经纤毛蛋白1的表达，随后获得中膜和外膜所定义的。在成人循环中，新的动脉通过预先存在的动脉血管结构的扩张或新生而产生。VEGF、其受体VEGFR2或关键细胞内信号传导介质的缺失导致动脉血管系统发育失败。在包括eNOS缺失的其他情况下或在诸如糖尿病和高胆固醇血症的疾病状态中注意到有缺陷的动脉生成，并且这种失败极大地促成了与这些疾病相关的发病率和死亡率。然而，整个过程是很少了解，目前还没有成功的方法来处理其在临床环境中的缺陷。了解调节动脉生成的分子机制将对我们理解主要心血管疾病的病理生物学和开发新的治疗方法来对抗它们非常有益。 在这个PPG中，我们提出了一个全面的方法来研究动脉生成的分子基础，并为该领域的治疗进展开发新的知识框架。为此，我们将研究一种新的信号通路，它似乎对动脉形成至关重要（项目1），研究一氧化氮和细胞外基质的贡献（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），并确定剪切应力和其他机械因素在启动AD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