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.
We generated a transgenic mouse line that overexpresses a transcription factor and resulted in increased arterial and collateral artery coverage of the heart. In this proposal we will discover whether activation of this transcriptional pathway can increase heart regeneration and reduce mortality following myocardial infarction of adult mice. Targeting the pathways activated by this transcription factor therapeutically in humans, may be able to improve survival in humans suffering from coronary artery disease, the leading cause of death worldwide.
