Elucidating the mechanisms of venous reprogramming during coronary development

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DESCRIPTION (provided by applicant): Coronary heart disease is the leading cause of death worldwide killing millions per year while tens of millions manage the disease medically or by undergoing surgical interventions. The disease results from pathology of the coronary arteries, but despite its impact on worldwide healthcare, surprisingly little is known about coronary artery development, which likely hampers efforts to improve available clinical treatments. The long-term goal of my research is to describe, at high resolution, all the cell differentiation and morphogenesis steps that produce coronary arteries from their progenitor cells during embryogenesis. I have recently identified the location of these progenitors in mice and described the developmental pathway leading to mature coronary arteries. Each step in the pathway occurred at stereotyped locations suggesting that position- specific cues trigger specific cell differentiation events. Coronary vessels begin as venous sprouts of the sinus venosus that de-differentiate as they migrate onto and invade the heart. Subsequently, the vessels differentiate into arteries, capillaries, or veins depending on their location within the heart. In this proposal, we will investigate the initial steps, sprouting and venous reprogramming, by carrying out the following aims: (1) Identify candidate sprouting and de-differentiation inducers by using microarrays to characterize the transcriptional profiles of cells located where these events occur. (2) Identify factors that induce endothelial de-differentiation by testing proteins isolated from these cells in an in vitro functional assay. (3) Test candidates from aims 1 and 2 for their role in vivo by assessing coronary vessel development in knockout animals or those treated with function-blocking antibodies or drugs. The initial part of the proposal will be carried out at Stanford University in Dr. Mark Krasnow's lab, an environment that has supported many innovative research projects that have led to fruitful independent careers. Here, I will carry out my immediate goal of finding a tenure- track position in which to complete the proposal's aims. At the conclusion, we will have identified the mechanisms underlying the first steps of coronary artery development providing insight into these novel processes as well as providing an experimental model for describing the remaining portions of the pathway. We will also be a step closer in understanding how to ectopically induce coronary vessels, which should be valuable information in furthering clinical developments. PUBLIC HEALTH RELEVANCE: Coronary artery disease is the leading cause of death worldwide and a significant healthcare burden for tens of millions who manage its symptoms medically or with surgical interventions. This proposal outlines experiments aimed at finding the proteins that induce coronary artery formation in the embryo so that they can be used to guide the development of therapeutics such as engineered vessels for bypass surgery or revascularization drugs.