Defining the Role of ROR2 in Right Ventricular Failure Pathogenesis

ABSTRACT The proposal in this application outlines a five-year career development plan to prepare the candidate, Dr. Jonathan Edwards, MD, for a career as an independent physician-scientist defining mechanisms of right ventricular failure (RVF). The research and development plans are carefully structured to expand Dr. Edwards’s

scientific foundation in cardiovascular research by providing technical training and expertise in in vitro cardiomyocyte biology, molecular biology, transgenic murine model development, and characterization of RV function in murine models. Dr. Edwards’s development plan will also strengthen his communication, leadership,

and collaboration skills through attendance of high yield coursework, workshops, and seminars. RVF is a significant health problem that is a strong predictor of death, and for which there are no proven therapies. The lack of human or animal work investigating molecular mechanisms of RVF, which could foster

the development of critically needed novel RVF therapies, is a significant gap in our field. I found that the fetal noncanonical WNT receptor ROR2 is strongly reactivated in the RV of patients with severe RVF and in mice with RVF from pressure overload. Further, this ROR2 activation was associated with upregulation of the ROR2/Ca2+

responsive protease calpain and target protein cleavage. I hypothesize that pathologic ROR2 expression is a novel and potentially targetable molecular driver of RVF and pathologic cardiomyocyte remodeling, which acts via calpain-mediated cytoskeleton and sarcomeric disruption and apoptosis in a subcellular Ca2+-dependent

manner. Three interrelated, but independent Specific Aims will address this hypothesis: 1) Determine the mechanistic role for Ror2 in in vitro cardiomyocyte cytoskeleton and sarcomeric disruption and apoptosis; 2) Determine if RV-specific Ror2 overexpression is sufficient to cause RVF; and 3) Determine if RV Ror2 expression

is necessary for pressure overload-induced RVF. This research training will be conducted under the mentorship of Dr. Zoltan Arany, MD, PhD (Director, Cell Biology, Physiology, and Metabolism), with co-mentorship by Dr. Benjamin Prosser, PhD (Associate Director, Penn Muscle Institute) at the University of Pennsylvania. Dr. Edwards has assembled an interdisciplinary

advisory committee with expertise in in vitro cardiomyocyte biology, molecular biology, translational science, Ca2+ regulation, WNT signaling, RVF murine modeling, transgenic animal model development, and leadership. Currently he is a board-eligible pediatric cardiologist, advanced clinical fellow in pediatric cardiomyopathy, heart

failure, and heart transplantation, and a postdoctoral fellow in the Arany laboratory. His long-term career goals are to serve as a physician-scientist with expertise in RV myocardial biology and the clinical management of pediatric patients with heart failure as an academic faculty member at a pediatric research hospital. Dr. Edwards

will benefit from his robust and balanced mentorship team, research environment, and unequivocal divisional and institutional commitment, all of which will support his path to independence.