The proposal describes a five-year training program for development of a research career in cardiovascular biology. The candidate is a cardiology fellow at the University of Pennsylvania, and is currently engaged in intensive basic science research. The proposed research will be carried out under the mentorship of Jonathan A. Epstein, M.D., a leader in the field of cardiac development who has trained numerous young investigators. An advisory committee of talented physician-scientists has also been assembled to offer guidance in career development and science. The research environment offers extensive resources, core facilities, and intellectual expertise. Therefore, it is an ideal trainin setting to develop the requisite skills in order to transition to an independent physician scientis. Participation in didactic courses and professional development seminars will enhance the educational success of the program. Organogenesis requires a fine balance between cell proliferation and differentiation. The perinatal heart is especially sensitive to this balance as tis is the window in which it transitions from proliferative to hypertrophic growth. Recent studies demonstrate that this is also the time period in which hearts can regenerate myocytes after injury. Therefore, an in-depth understanding of these processes is likely to be of considerable interest. Hopx is a transcription co-factor, and a cohort of Hopx-null embryos display late gestation cardiac myocyte hyperplasia, suggesting a critical role for Hopx in regulating embryonic myocyte proliferation. However, the proteins that Hopx interacts with and the transcriptional programs it regulates in modulating cardiac myocyte proliferation remain largely a mystery. Novel genetic tools developed by the candidate will facilitate investigation of these processes, and the aims of the proposal are: 1. Test the hypothesis that Hopx is a subunit of the NuRD complex in embryonic myocytes. 2. Test the hypothesis that Hopx-containing complexes function to inhibit embryonic myocyte proliferation by directly binding the regulatory regions of proliferation- related genes. 3. Test the hypothesis that the interaction between Hdac2 and Hopx is of functional consequence in vivo in a tissue specific manner and hence facilitates Hopx-mediated hypertrophy. Recent studies have also identified specific Hopx expression in adult intestine and hair follicle stem cells. Therefore, it is anticipated that concepts gleaned from the investigation of those well-characterized populations, coupled with mechanistic studies in embryonic cardiac progenitor cells will build a strong platform for the applicant to succeed as an independent scientist dissecting adult cardiac regenerative responses.
For years, it was thought that the heart possessed no inherent ability to repair itself, but recent studies have shown that the heart has a small window in which it can regrow damaged muscle following an injury. Boosting the potential of the heart to repair itself is an attractive means for enhancing heart function in light of the epidemic of heart disease in the United States. However, the exact identity and full ability of cells responsible for heart regeneration remains poorly defined, and understanding how heart cells grow and divide will hopefully provide a platform to develop novel therapies to boost the function of failing heart or even heal itself after a large heart attack!