Arteriogenesis and Arterial Branching

描述(申请人提供)：动脉系统的形成是一系列复杂的步骤，到目前为止还知之甚少。这一过程在很大程度上是由血管内皮生长因子(VEGF)驱动的，并导致在胚胎发育期间和成年组织中形成新的动脉。在之前的融资周期中，我们发现了新的监管步骤，这些步骤似乎在调控动脉生长和分支方面发挥了核心作用。目前的建议旨在加深我们对这些事件的了解，并开始开发新的治疗策略，以帮助数百万患有缺血性心血管疾病的人。特别是，我们建议探索一个新的控制点的作用，它影响内皮细胞的两个主要信号输入-生存/血管维持信号(Akt/eNOS)和血管生长信号(ERK)。详细了解这一调控是如何实现的，将对开发能够[促进新动脉生长]的药物大有裨益。此外，我们建议探索我们实验室发现的另一个关于血管内皮生长因子信号的新方面--血管内皮生长因子受体2(VEGFR2)信号的空间调控。这些研究将探索VEGFR2信号在细胞中的位置，是什么控制了它的贩运，以及这一过程是如何受到调控的。最后，有了这些知识，我们将探索胆固醇水平升高是如何损害血管内皮生长因子信号的，以及可以采取哪些步骤来克服这一点。综上所述，这是一项全面的计划，旨在加深我们对动脉形成这一关键生物学过程的理解，这可能会导致开发治疗冠状动脉和外周动脉疾病的新治疗方法。

DESCRIPTION (provided by applicant): Formation of the arterial system is a complex series of steps that is, as yet, poorly understood. The process is largely driven by vascular endothelial growth factor (VEGF) and results in formation of new arteries during embryonic development and in adult tissues. In the previous funding cycle we have uncovered novel regulatory steps that appear to play central roles in regulation of arterial growth and branching. The current proposal is aimed at further our understanding of these events and beginning development of novel therapeutic strategies that can help millions of people with ischemic cardiovascular diseases. In particular, we propose to explore the role of a novel control point that affects two major signaling input to endothelial cells- the survival/vessel maintenance signal (Akt/eNOS) and the vessel growth signal (ERK). A detailed understanding of how this regulation is accomplished would go a long way to developing drugs that could [promote growth of new arteries. In addition, we propose to explore another novel aspect of VEGF signaling discovered by our lab- spatial control of VEGF receptor 2 (VEGFR2) signaling. These studies will explore where in the cell VEGFR2 signals, what controls its trafficking and how that process is regulated. Finally, with this knowledge in hand, we will explore how elevated cholesterol levels impair VEGF signaling and what steps can be taken to overcome that. Taken together, this is a comprehensive program aimed at further our understanding of a key biological process, arteriogenesis, that may result in development of new therapeutic approaches to treatment of coronary and peripheral; arterial diseases.