Arteriogenesis and arterial branching

描述(由申请人提供)：动脉树的生长和分支是潜在的发育、器官生长和从有害的侮辱中恢复的基本过程。然而，尽管它具有明显的生物学重要性，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，联结蛋白是一种单结构域的PDZ蛋白，被认为参与了细胞内信号复合体的组装，在动脉形成和分支形态发生的调节中发挥着重要作用。具体地说，我们已经证明，在小鼠中，联结蛋白基因的纯合缺失会导致动脉系统发育不良的小鼠(直管鼠)分支明显减少，并损害成人动脉生成。值得注意的是，缺陷仅限于动脉系统，而不是静脉系统。这种小鼠模型的可获得性首次为我们提供了设计一个实验程序的能力，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)充分表征联结蛋白基因敲除小鼠聚焦的表型和这种缺陷的动脉特异性，2)确定哪种细胞类型对异常的动脉发生和分支形态发生负责，3)确定导致这些事件的分子事件。综合起来，这三个目标将提供对第一个已知的动脉起源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，该提案将重点放在成人动脉生成上。人们希望，更好地了解成人组织中的动脉生长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.