Document text
Principal Investigator: Jonathan Joseph Edwards
Organization: CHILDREN'S HOSP OF PHILADELPHIA
Fiscal Year: 2024
Award: $131,400
Funding agency: National Heart Lung and Blood Institute
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.
Terms: <AAV9 delivery><AAV9 mediated delivery><AAV9 vector delivery><AAV9 viral delivery><AAV9 virus to deliver><Actins><Acute><Advisory Committees><American><Animals><Apoptosis><Apoptosis Pathway><Biology><CRISPR><CRISPR/Cas system><Ca2+-Activated Protease><Calcium-Activated Neutral Protease><Calcium-Activated Neutral Proteinase><Calcium-Activated Protease><Calcium-Dependent Neutral Protease><Calcium-Dependent Neutral Proteinase><Calpain><Cardiac Muscle Cells><Cardiac Myocytes><Cardiac Transplantation><Cardiocyte><Cardiovascular><Cardiovascular Body System><Cardiovascular Organ System><Cardiovascular system><Cell Surface Receptors><Cellular Matrix><Cellular biology><Cessation of life><Childhood Cardiomyopathy><Clinical><Clinical Management><Clustered Regularly Interspaced Short Palindromic Repeats><Collaborations><Common Rat Strains><Communication><Complementary DNA><Complex><Complex thinking><Critical Thinking><Cytoskeletal Gene><Cytoskeletal Proteins><Cytoskeletal System><Cytoskeleton><DNA Molecular Biology><Data><Death><Desminase><Development><Development Plans><Development and Research><Doctor of Philosophy><Domestic Rabbit><Echocardiogram><Echocardiography><Educational workshop><Eligibility><Eligibility Determination><Environment><Epidemiology><Esteroproteases><Evaluative Thinking><Expression Signature><F-Actin><FLN1><FLNA><FLNA gene><Faculty><Failure><Filamentous Actin><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Fostering><Foundations><Funding><Gene Expression Profile><Genes><Goals><Guide RNA><Health><Heart><Heart Grafting><Heart Muscle Cells><Heart Transplantation><Heart Vascular><Heart failure><Heart myocyte><Histology><Hospitals><Human><Human Rights><Immunoblotting><In Vitro><Institution><Intermediary Metabolism><Investigators><Knowledge><Laboratories><Leadership><Left><Ligands><LoxP-flanked allele><Malignant Cell><Mediating><Mentors><Mentorship><Metabolic Processes><Metabolism><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Molecular Biology><Murine><Mus><Muscle><Muscle Cells><Muscle Tissue><Myocardial><Myocytes><Neonatal><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neurons><OPD1><OPD2><Oryctolagus cuniculus><Papain-Like Cysteine Protease><Pathogenesis><Pathologic><Pathology><Pathway interactions><Patients><Pediatric Cardiomyopathy><Pediatric Research><Pennsylvania><Peptidases><Peptide Hydrolases><Ph.D.><PhD><Phenotype><Physicians><Physiology><Postdoc><Postdoctoral Fellow><Programmed Cell Death><Protease Gene><Proteases><Protein Cleavage><Proteinases><Proteolysis><Proteolytic Enzymes><Protocol Screening><Pulmonary Artery><Pulmonary artery structure><R & D><R&D><Rabbits><Rabbits Mammals><Rat><Rats Mammals><Rattus><Receptor Protein><Recombinants><Regulation><Research><Research Associate><Research Personnel><Research Training><Researchers><Role><Sampling><Scientist><Structure><Task Forces><Technical Expertise><Testing><Training><Training Programs><Transgenic Animals><Transgenic Organisms><Translational Research><Translational Science><Transthoracic Echocardiography><Treatment Failure><Universities><Up-Regulation><Upregulation><Ventricular><WNT Signaling Pathway><WNT signaling><WNT5A><WNT5A gene><Western Blotting><Western Immunoblotting><Work><Workshop><adeno-associated viral vector 9 delivery><adeno-associated virus 9 delivery><advisory team><alpha Actinin><animal model development><cDNA><cancer cell><cardiac failure><cardiac graft><cardiomyocyte><cardiomyopathy in childhood><cardiomyopathy in children><career><career development><cell biology><child patients><childhood myocardial disease><children with cardiomyopathy><circulatory system><death risk><developmental><differential expression><differentially expressed><early-onset cardiomyopathy><epidemiologic><epidemiological><extracellular><fetal><filamin A, alpha><flow cytophotometry><floxed><floxed allele><gRNA><gain of function><gene expression pattern><gene expression signature><heart sonography><heart transplant><hemodynamics><in vivo><in vivo Model><insight><intracellular skeleton><knock-down><knockdown><loss of function><member><model development><model developments><mortality><mortality risk><mouse model><murine model><muscular><neuronal><novel><overexpress><overexpression><pathway><pediatric cardiologist><pediatric patients><post-doc><post-doctoral><post-doctoral trainee><pressure><protein blotting><public health relevance><receptor><research and development><research associates><response to therapy><response to treatment><right heart failure><right sided heart failure><right ventricle failure><right ventricular failure><right ventricular heart failure><shRNA><short hairpin RNA><skills><small hairpin RNA><social role><technical skills><therapeutic response><therapeutic target><therapy failure><therapy response><transcriptional differences><transcriptional profile><transcriptional signature><transgenic><translation research><translational investigation><treatment response><treatment responsiveness><α-Actinin>