Arteriogenesis and arterial branching

描述（由申请人提供）：动脉树的生长和分支是发育、器官生长和从有害损伤中恢复的基本过程。尽管具有明显的生物学重要性，但人们对这些事件的分子性质及其调控知之甚少。我们最近发现，连接蛋白是一种单域PDZ蛋白，被认为参与细胞内信号复合物的组装，在动脉发生和分支形态发生的调节中起重要作用。具体来说，我们已经证明了小鼠中连接蛋白基因的纯合缺失会导致小鼠动脉系统发育不全，分支明显减少（“直管小鼠”），并且成年动脉发生受损。值得注意的是，这种缺陷仅限于动脉系统而不是静脉系统。这种小鼠模型的可用性首次为我们提供了设计实验程序的能力，以获得对动脉生长生物学的新的和基本的见解。因此，在这项授权中，我们建议：1)充分表征连接蛋白敲除小鼠聚焦的表型和该缺陷的动脉特异性；2)确定哪种细胞类型负责异常动脉发生和分支形态发生；3)确定负责这些事件的分子事件。综上所述，这三个目标将提供第一个已知的动脉源性分支缺陷的全面评估，并将阐明血管生物学中尚未被探索和理解的方面。由于其明显的现实意义，该建议将重点放在成人动脉发生上。希望对成人组织中动脉生长的更好理解将加速治疗性血管生成策略的发展。

DESCRIPTION (provided by applicant): Growth and branching of the arterial tree is a fundamental process underlying development, organ growth and recovery from a noxious insult. Despite its obvious biological importance, however, little is known about the molecular nature of these events and their regulation. We have recently discovered that synectin, a single domain PDZ protein, thought to be involved in the assembly of intracellular signaling complexes, play an important role in regulation of arteriogenesis and branching morphogenesis. Specifically, we have demonstrated that homozygous deletion of synectin gene in mice results in mice with under-developed arterial system with markedly reducing branching ("the straight tube mouse") and impaired adult arteriogenesis. Remarkably, the defect is limited to the arterial and not the venous system. The availability of this mouse model provides us for the first time with the ability to devise an experimental program to gain new and fundamental insights into biology of arterial growth. In this grant, therefore, we propose to 1) Fully characterize the phenotype of synectin knockout mice focusing and arterial specificity of this defect 2) Establish which cell type is responsible for the abnormal arteriogenesis and branching morphogenesis and 3) Determine molecular events responsible for these events. Taken together, these three Aims will provide a comprehensive evaluation of the first known arteriogenic branching defect and will illuminate poorly explored and understood aspect of vascular biology. The proposal focuses on adult arteriogenesis because of its obvious practical significance. It is hoped that a better understanding of arterial growth in adult tissues will accelerate development of therapeutic angiogenesis strategies.