The goal of this proposal is to develop the principal investigator (PI) into an independent physician scientist in the field of cardiovascular research. The PI has previously obtained PhD training in developmental biology and has obtained additional training in basic and translational cardiovascular research. At this point in time, the I has completed clinical training in Internal Medicine and Clinical Cardiology, and is currently enrolled in the ABIM sponsored Advanced Heart Failure and Cardiac Transplantation fellowship. The following 5-year career development plan will provide the PI formal training in Immunology and ongoing laboratory training in the study of cardiac injury and angiogenesis. At the conclusion of this award period, the PI will have acquired the skills necessary to become an independent and successful physician scientist. Dr. Douglas Mann, Chief of Cardiology at Washington University, will mentor the PI. Dr. Mann is a recognized leader in myocardial inflammation and has a tremendous breadth of experience in cardiovascular research. His expertise spans from basic to clinical science where he has defined the role of pro-inflammatory cytokines in heart failure and spearheaded a clinical trial based on his results. As such, he serves as a perfect example of a successful physician scientist that is able to translate basic science research into the clinical arena. The PI will take advantage of this mentorship along with the enormous basic science and clinical resources available at Washington University (a nationally recognized premier academic institution) to define a new area of clinically relevant basic science research. Ischemic heart disease is the leading cause of heart failure and mortality in the industrial world. Despite improvements in therapy, a growing percentage of patients are not optimally treated with traditional revascularization procedures and consequently have high mortality rates. Previous studies have demonstrated that a subgroup of patients will develop collateral vasculature, which effectively serve as natural bypass grafts that supply blood flow to ischemic areas of the heart. The presence of coronary collaterals is associated with reduced rates of cardiac mortality and adverse events. Due to the lack of animal models, little is known regarding how coronary collaterals grow within the heart. To address this issue, we recently developed a model of coronary collateral growth in the adult mouse. Surprisingly, we demonstrated that classic pro- angiogenic growth factors are not induced in this model, and instead, our data suggests that a specific macrophage lineage (which is derived from the embryo) controls coronary collateral growth. In this proposal, we will test the hypothesis that embryonic-derived macrophages are critical regulators of coronary development in the embryo and collateral growth in the adult heart. In addition, we will define the mechanism by which embryonic-derived macrophages stimulate coronary growth. The identification of a specific macrophage lineage capable of growing coronary collateral vasculature would have broad implications with respect to the development of novel therapies for patients with ischemic heart disease.
This career development proposal has two important components that will benefit public health. The first is the development of the principle investigator into a physician scientist, which is a uniquely trained medical doctor who by treating patients and conducting research identifies important gaps in our medical knowledge and subsequently investigates new therapies. The second is the identification of a previously unrecognized cell type that contributes towards promoting formation and growth of coronary blood vessels. Understanding mechanisms by which these cells stimulate growth of the heart's arteries will potentially provide new therapies for patients with coronary artery disease.