Investigating the Role of Dach1 in Artery Specification and Collateral Artery Development

冠状动脉疾病是世界范围内主要的死亡原因，新的 治疗策略可以降低死亡率。侧支动脉将动脉相互连接 并为冠脉循环提供多种途径。在冠心病患者中， 那些侧支动脉发达的患者死亡率较低。 不幸的是，由于我们对动脉形成的基本机制缺乏了解。 增长，没有治疗方法来增加侧支动脉覆盖率。 为了找到调节动脉发育的新基因，我们产生了一个 在内皮细胞中高表达转录因子Dach1的转基因小鼠品系。 利用全鼠免疫染色和共聚焦显微镜，我们发现Dach1 Over 在发育过程中，表达基因的小鼠的动脉和侧支动脉覆盖率增加。 通过体外和体内实验的结合，我们进一步发现Dach1超过 表达增强表达增强动脉基因的表达增强而降低 静脉基因表达支持Dach1诱导动脉规范的模型 内皮细胞。 这项建议的目标是1)了解Dach1激活的通路是如何 增加动脉细胞规格和2)测试是否增加侧支动脉覆盖率 过表达Dach1可以预防心肌梗死。我们会找到起作用的因素 在Dach1下游通过遗传学或药理学启动动脉规范 Dach1过表达背景和可视化动脉中的抑制候选因子 使用共聚焦显微镜形成。此外，我们还将采用小鼠冠状动脉结扎术 模型测试过量表达Dach1的成年小鼠是否可以在 结扎和提高存活率。回答这些问题将阐明新的分子 冠状动脉病变患者可靶向治疗的动脉生长调节因子 疾病。 这项研究将在斯坦福大学克里斯蒂·红马博士的实验室进行 大学。教师导师和学院都非常适合科学和职业生涯。 申请人的发展情况。具体地说，申请者将受益于大量的机会 对于科学报告和写作练习，初级研究生的指导，访问 为了最先进的小鼠遗传学实验设施，每周与Dr。 红马，并与将领导外科研究的丹·伯恩斯坦博士密切合作。

Coronary artery disease is the leading cause of death worldwide and development of new therapeutic strategies could reduce mortality. Collateral arteries connect arteries to one another and provide multiple routes for coronary circulation. In patients with coronary artery disease, those that have well-developed collateral arteries have a reduced rate of mortality. Unfortunately, due to our poor understanding of the basic mechanisms responsible for artery growth, there are no therapies to increase collateral artery coverage. In order to find novel genes which regulate artery development, we generated a transgenic mouse line that over expressed the transcription factor Dach1 in endothelial cells. Using whole mouse immunostaining and confocal microscopy, we found that Dach1 over expression mice had increased artery and collateral artery coverage during development. Through a combination of in vitro and in vivo experiments we went on to find that Dach1 over expression increased expression increased the expression of arterial genes and decreased venous gene expression supporting a model where Dach1 induces the specification of artery endothelial cells. The goal of this proposal is to 1) understand how the pathway activated by Dach1 increases arterial cell specification and 2) test if increasing collateral artery coverage though Dach1 overexpression can protect against myocardial infarction. We will find the factors that act downstream of Dach1 to initiate artery specification by genetically or pharmacologically inhibiting candidate factors in the Dach1 overexpression background and visualizing artery formation using confocal microscopy. In addition, we will use the mouse coronary artery ligation model to test if adult mice over expressing Dach1 can make more collateral arteries post- ligation and increase survival. Answering these questions will elucidate new molecular regulators of artery growth that could be targeted therapeutically in patients with coronary artery disease. This research will be conducted in the laboratory of Dr. Kristy Red-Horse at Stanford University. Both the faculty mentor and institution are well suited for the scientific and career development of the applicant. Specifically, the applicant will benefit from abundant opportunities for scientific presentations and writing practice, mentorship of junior graduate students, access to state of the art facilities for experimenting with mouse genetics, weekly meetings with Dr. Red-Horse, and close collaboration with Dr. Dan Bernstein who will lead the surgical studies.