Project Summary/Abstract This is an application for a K08 award for Dr. Shah Ali, MD, an Instructor in Cardiology at the University of Texas Southwestern (UTSW), for his transition from Instructor to independent investigator in basic cardiovascular biology with a focus on cardiac regeneration. He has completed residency training in Internal Medicine at the University of California San Francisco and fellowship training in Cardiology at UTSW. The research in this proposal will be conducted in the laboratory of Dr. Hesham Sadek, a leading expert in the field of cardiac regeneration and an ideal mentor with significant training experience. In addition, an Advisory Committee that includes Dr. Eric Olson, a renowned expert in cardiac developmental biology, will provide biannual constructive criticism of data, hypotheses, and proposed experiments in a written manner as well as career guidance and development. The proposal described herein will investigate the molecular mechanisms of neonatal heart regeneration in mice with an aim at translating these findings to humans to generate novel therapies to treat heart diseases. Although the mammalian heart is known to be a mostly quiescent organ whose primary parenchymal cell – the cardiomyocyte – is cell cycle-arrested in adults, recent pioneering studies from the laboratory of Dr. Sadek have characterized a phenomenon of complete cardiac regeneration in neonatal mice. After resection of the ventricular apex or surgically-induced myocardial infarction (MI), mice younger than one week of age exhibit complete cardiomyocyte renewal, in stark contrast to adult mice that develop a fibrotic scar due to failure to achieve meaningful cardiomyogenesis. A fate-mapping approach showed that existing cardiomyocytes divide to generate new cardiomyocytes after neonatal injuries. Based on the above findings, we hypothesized that there are cardiotropic factors within the young mouse heart that elicit the robust cardiomyocyte proliferation after neonatal MI. Our preliminary data identifies insulin- like growth factor binding protein, IGFBP3, as a cardiomyocyte mitogen that enables cardiomyocyte division. Intriguingly, this factor is not expressed in the heart in the absence of injury or during development, suggesting that it is part of a specific injury-induced signaling pathway. The specific aims propose to: 1) identify and characterize the cell that secretes IGFBP3 in response to injury, 2) determine whether IGFBP3 is necessary for neonatal regeneration and/or sufficient to promote cardiomyocyte renewal after adult MI, and 3) determine whether IGFBP3 utilizes IGF signaling to stimulate cardiomyocyte division. Ultimately, the training and research plan outlined here will support Dr. Ali as he achieves independence as a physician-scientist-cardiologist. As an independent PI, Dr. Ali will study the mechanisms that mediate neonatal heart regeneration to inform the development of novel therapeutics for adult heart disease, a logical extension of his K08 proposal.

Project Narrative Heart disease is a leading cause of death in the U.S., partly due to the inability of muscle cells in the adult heart to divide. In sharp contrast, muscle cells in young mice divide robustly after a heart attack and can regenerate. Completion of the proposed studies will identify proteins in the young mouse heart that promote cardiac cell division, with the hope of applying these findings to treat human cardiovascular diseases.