This research proposal outlines a 5-year career development plan for James Rhee, M.D., Ph.D., re- search fellow at the Cardiovascular Research Center at Massachusetts General Hospital (MGH) and Instructor in Anesthesia at Harvard Medical School (HMS), to achieve independence as a principal investigator under the mentorship of Anthony Rosenzweig, M.D., Chief of Cardiology at MGH and Professor of Medicine at HMS. Im- portantly, Dr. Rosenzweig has a strong track record of mentoring scientists with over 50 trainees holding aca- demic faculty positions, many in leadership roles. An advisory committee composed of Fumito Ichinose, Pro- fessor at HMS; Jianren Mao, Vice-Chair of Research; and Saumya Das, Associate Professor of Medicine, along with collaboration from Dr. Matthias Nahrendorf (Director of the Mouse Imaging Program, Center for Sys- tems Biology), will lend expertise on models of biomarker discovery and validation, cardiac stress and inflam- mation and imaging, and career development. Dr. Rhee will take full advantage of the world class environment of the Rosenzweig lab and surrounding MGH and Harvard Medical School campuses in addressing the ambi- tious aims of this proposal. This plan allows Dr. Rhee to develop expertise in cardiovascular proteomics and ischemia reperfusion injury that builds upon his lengthy research experiences in cellular and molecular biology and his clinical role in the critical care of high acuity patients. Cardioprotection and effective adaptation or ?remodeling? of the heart after injury is a complex process involving cross-talk between cardiomyocytes and many other cell types. A balance between clearing dead or damaged cells and enhancing the viability of surviving cardiac and non-cardiac tissue, such as vascular endo- thelium, is essential for maintaining homeostasis and recovering function. Optimal remodeling of the myocardi- um after injury is largely dependent on appropriate sequential activation of an immune program involving dif- ferent subtypes of leukocytes. The candidate has used plasma samples from ?good? and ?poor? remodelers after myocardial infarction to identify secreted factors that may limit acute injury and promote healing. Of the more than 1300 circulating proteins profiled, one of the highest scoring candidates, by both statistical signifi- cance and fold change, is the chemokine Family with sequence similarity 3 member D (FAM3D). Presented in this proposal are compelling preliminary data to suggest that splenic FAM3D exerts acute protection, in the form of dramatically reduced infarct size, after ischemia-reperfusion injury through anti-inflammatory mecha- nisms. Dr.Rhee lays out a comprehensive plan to characterize the completely novel cardiovascular impact of this molecule. He will employ robust in vivo gain- and loss-of-function studies to better understand the role of FAM3D. These studies will lead to a better understanding of ischemic injury and the ensuing inflammation, and to new therapeutic insight into how to limit and treat these conditions in the heart and other vital organs.
Cardiovascular disease is the leading cause of death in the world and the United States, and heart attack (myocardial infarction) leading to adverse remodeling and heart failure carries significant morbidity and mortality. This career development proposal will allow the candidate, a scientist with a clinical directive to maintain organ perfusion in his patients, to establish expertise and independent investigation in the crucial molecular links between cardiac ischemia and inflammation. These studies will reveal pathways activated by myocardial ischemia and reperfusion, and facilitate the development of possible therapy in acute and chronic settings of heart disease.