The Molecular Mechanisms of KLF2 Regulation and Function in Endothelial Cells

Case Western Reserve University, Cleveland OH

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Abstract

DESCRIPTION (provided by applicant): This proposal describes a comprehensive five year training program for the development of the Principal Investigator's (PI) academic career in Cardiovascular Medicine. The PI has completed clinical training in Cardiology at Massachusetts General Hospital (MGH) and will now embark upon a rigorous training program that is tailored to provide the experience, mentorship, and resources required for an eventual independent research career. This program provides the PI with the experience to gain further in-depth knowledge and expertise in Molecular and Transcriptional Biology. Dr. Mukesh K. Jain, Director of the Case Cardiovascular Research Institute (CVRI), will mentor the PI's scientific development. As detailed in this proposal, the research environment is ideal and Dr. Jain has proven to be an exemplary mentor. The training will be enhanced by collaborations with the laboratories of Dr. John Schwarz, Dr. John Lowe, and Dr. Thomas Michel who will provide their respective expertise in the areas of in vivo study of MEF2 transcription factors, laminar flow/sheer stress and vasoreactivity experiments. In addition, an advisory committee of renowned medical scientists will provide scientific and career guidance. This highly structured career development plan also includes relevant coursework/symposia and conferences. The project is designed to elucidate the role of the transcription factor KLF2 in endothelial biology. Preliminary work shows that this factor is expressed in endothelial cells, is induced by laminar flow, and is a potent and novel transcriptional regulator of factors which determine the anti-thrombotic nature of healthy endothelium. Based of these observations, it is hypothesized that KLF2 is a key molecular switch involved in the regulation of endothelial function and vascular homeostasis in health and disease. The Specific Aims of this proposal are: 1) To determine the molecular basis of KLF2 regulation in vitro and in vivo. 2) To determine the mechanistic basis of KLF2's ability to induce eNOS gene expression. 3) To assess for effects of endothelial specific KLF2 overexpression on gene expression and vasoreactivity in vivo. Relevance: Atherosclerosis and cardiovascular disease is a major clinical problem affecting over 13 million people. The research proposed in this project aims to improve our understanding of the molecular mechanisms of cardiovascular disease with the ultimate goal of developing novel therapies for treatment.