Modulation of epigenetically controlled cardiac repair mechanisms by ethanol

总结抽象

SUMMARY ABSTRACT This proposal describes a 5 year training program for the development of an independent academic career in the Biomedical Sciences. The PI completed his PhD training in Pharmacology at Loyola University Chicago and additional post-doctoral training in Regenerative Medicine in the Feinberg Cardiovascular Research Institute (FCVRI) at Northwestern University. The FCVRI provides an ideal setting by incorporating expertise from diverse resources into customized programs in order to maximize the potential for trainees establishing a scientific niche from which a successful, independent academic career can be launched. This proposal will expand upon the PI's scientific and analytical skills through a unique integration of interdepartmental resources. This program will assess how chronic ethanol consumption modulates the endothelial epigenome to alter functional and survival outcomes following acute myocardial infarction (AMI). Dr. Raj Kishore (Associate Professor of Medicine) will mentor the PI's scientific development and does so as a recognized leader in the field of Regenerative Medicine with a formidable record of training academically successful independent scientists. Additionally, the program will enlist the expertise of Dr. Lifang Hou (Associate Professor of Preventative Medicine) and Dr. Gangjian Qin (Assistant Professor of Medicine) as co- mentors, who are both well-respected scientists within their respective fields. Lastly, several highly-regarded biomedical scientists will form a developmental advisory committee alongside an expert alcohol contributor (Dr. Elizabeth Kovacs) to provide scientific and career advice throughout the PI's development. The research proposal focuses on how ethanol modulates the epigenomic programs in cell types involved in myocardial ischemic repair. Preliminary data reveals that chronic ethanol alters expression patterns of specific genes (i.e. eNOS and MMP9) in endothelial progenitor cells (EPCs): an important cell type involved in post-ischemic repair. Evidence shows that chronic ethanol consumption impacts cardiac function following an AMI and also alters various epigenetic marks in endothelial cells (ECs). Proposed experiments will utilize a chronic ethanol consumption model to explore cellular/epigenetic changes that manifest as altered outcomes following AMI. The specific aims include: 1) To determine why disparate levels of prior chronic ethanol consumption produce differential effects on cardiac function following AMI, 2) To investigate the mechanistic basis and functional impact of ethanol's modulation of the epigenomic fingerprint in CECs/EPCs, 3) What role does ethanol-mediated epigenetic regulation of MMP9 and eNOS expression play in EPC-mediated myocardial repair following AMI? This is the first mechanistic analysis of ethanol-induced epigenomic regulation in the heart and uses relevant models that mimic the circumstances of human patients.