Phenotype, dynamics and activation of myocardial B lymphocytes in response toischemia/reperfusion injury

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Project Summary/Abstract: 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 PI has completed clinical training in Internal Medicine, Cardiology, Advanced Heart Failure and Cardiac Transplant and he is a post-doctoral research fellow (supported by T32 HL007081) in Dr. Douglas Mann’s Lab. 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. 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 be the primary mentor of 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 (an internationally recognized premier academic institution) to define a new area of clinically relevant basic science research. Heart failure is one of the leading causes of disability and mortality related to cardiovascular disease and single handedly drains almost 2% of total US healthcare spending. Recent evidence suggests that modulation of myocardial B lymphocytes might provide an innovative therapeutic approach to reduce the development of heart failure in patients that experienced heart damage. Unfortunately, our current understanding of the biology of myocardial B lymphocytes is minimal. We recently found that myocardial B lymphocytes are much more heterogeneous than what was previously appreciated. We identified several subgroups of myocardial B cells and we showed that different sub-groups of myocardial B cells respond differently to acute heart damage. In this proposal, we will test the hypothesis that the myocardium harbors dynamic subpopulations of B lymphocytes with different ontogeny, that produce specific responses to acute cardiac injury, and that B cells have antagonistic roles within the amplification/resolution balance of the inflammatory response to cardiac damage.