This proposal describes a research plan designed to elucidate the intersection between transcription factor KLF2 and PPARalpha 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 PI 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. Furthermore, our studies demosntrate 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 this proposal, we will explore the novel link between KLF2 and PPARalpha in the context of endothelial gene expression and function. Then key observations will be confirmed in vivo using genetically modified mice through gain and loss of function studies. All studies have begun in the K99 phase and will continue into the ROO 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. Continuing support of this project via a ROO award would play a pivotal and requisite role in the Pi's development into an independent investigator. The PI has completed requisite additional training during the K99 phase and is now transitioning toward becoming an NIH-funded independnet investigator.
The molecular mechanisms regulating the diverse function of endothelial cells remain poorly understood. The results of the studies outlined in this proposal will provide insights regarding the cross talk between two key genetic pathways in regulating endothelial function under physiologic and pathologic states. The results of these studies may provide the foundation for novel therapies directed at vascular inflammation diseases.
