KLF2, PPARalpha and Atherothrombosis

该提案描述了一项研究计划，旨在阐明转录因子 KLF 2和PPARalpha在维持血管稳态中的作用心血管疾病是导致 死亡在美国。血管内皮，包括血液和血管之间的界面， 身体的其他组织在健康和疾病中发挥着重要作用。内皮功能障碍是一个关键 在多种心血管疾病的发展和进展中的病理生理事件。主要研究者有 提出了涉及KLF 2在调节内皮促炎中的关键作用的原始观察结果， 活化和血栓形成功能。鉴于其在血管稳态中的关键作用， KLF 2在内皮生物学中的功能具有重要的科学意义。此外，我们的研究 证明过氧化物酶体增殖物激活剂受体α（PPARalpha）激活可增加KLF 2 表情PPARalpha活化已显示出抗炎和抗血栓形成 通过调节关键内皮基因的表达来调节其特性。在本建议书中，我们将探讨 在内皮基因表达和功能的背景下，KLF 2和PPARalpha之间的新联系。然后 关键的观察结果将在体内使用转基因小鼠通过功能的获得和丧失得到证实。 问题研究所有研究均已在K99阶段开始，并将继续进入ROO阶段。重要的是这些 研究将为KLF 2如何调节内皮功能提供重要的见解，也可能作为 限制/预防血管疾病（包括动脉粥样硬化）的新治疗策略的基础。 通过ROO奖继续支持这个项目将在Pi的 发展成为独立调查员。PI已完成必要的额外培训 K99阶段，现在正在向成为NIH资助的独立调查员过渡。

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.