Arteriogenesis and Arterial Branching

描述（由申请人提供）：动脉系统的形成是一系列复杂的步骤，迄今为止，人们对其知之甚少。这一过程主要由血管内皮生长因子（VEGF）驱动，并在胚胎发育和成人组织中形成新动脉。在之前的融资周期中，我们发现了新的调控步骤，这些步骤似乎在动脉生长和分支的调控中起着核心作用。目前的建议旨在进一步了解这些事件，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，我们建议探索影响内皮细胞两种主要信号输入的新控制点的作用-生存/血管维持信号（Akt/eNOS）和血管生长信号（ERK）。详细了解这种调节是如何完成的，将对开发促进新动脉生长的药物大有帮助。此外，我们建议探索我们实验室发现的VEGF信号传导的另一个新方面- VEGF受体2 （VEGFR2）信号的空间控制。这些研究将探索细胞中VEGFR2信号的位置，是什么控制着它的运输，以及这个过程是如何被调节的。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VEGF信号的，以及采取什么措施来克服这一点。综上所述，这是一个综合性的项目，旨在进一步了解一个关键的生物学过程，动脉形成，这可能会导致新的治疗方法的发展，以治疗冠状动脉和外周；动脉疾病。

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.