This proposal describes a research plan designed to elucidate the role of the transcription factor KLF2 in maintaining vascular homeostasis. Cardiovascular disease is the leading cause of death in the United States. The vascular endothelium, comprising the interface between blood and the other tissues of the body, plays a fundamental role in health and disease. Endothelial dysfunction is a key pathophysiologic event in the development and progression of diverse cardiovascular diseases. The candidate has made original observations implicating the critical role of KLF2 in regulating endothelial pro-inflammatory activation and thrombotic function. Given its pivotal role in vascular homeostasis, a greater understanding of the function of KLF2 in endothelial biology is of significant scientific interest. In this proposal, Specific Aim 1 is designed to delineate the molecular basis for KLF2's ability to regulate thrombomodulin under basal and laminar flow conditions. Furthermore, our studies demonstrate that activation of peroxisome proliferator activator receptor alpha (PPARalpha) increases KLF2 expression. PPARalpha activation has been shown to exhibit anti-inflammatory and anti-thrombotic properties through regulating expression of critical endothelial genes.
In Specific Aim 2, we will explore this novel link between KLF2 and PPARalpha in the context of endothelial gene expression and function.
In Specific Aim 3, key observations will be confirmed in vivo using transgenic mice through gain and loss of function studies. All studies will begin in the mentored phase and will continue into the independent phase. Importantly, these studies will provide significant insights into how KLF2 regulates endothelial function and may also serve as the basis of novel therapeutic strategies to limit/prevent vascular diseases, including atherosclerosis. Support of this project via a K99/R00 award would play a pivotal and requisite role in the candidate's development into an independent investigator. His immediate goal is to solidify his research experience through additional intensive mentorship, technical training, and broad intellectual development that will result directly from this proposal. A highly structured career development plan is an intrinsic component of this proposal and is designed to greatly enhance accomplishment of the candidate's long-term career goal: independent performance of vascular biology research as an NIH-funded faculty member.
