KLF2, PPARalpha and Atherothrombosis

这项提案描述了一项旨在阐明转录因子之间的交集的研究计划。 KLF2和PPARα在维持血管内稳态中的作用心血管疾病是导致 美国的死亡案例。血管内皮细胞，包括血液和血管之间的界面 身体的其他组织，对健康和疾病起着基础性的作用。内皮功能障碍是一个关键 多种心血管疾病发生发展过程中的病理生理学事件。少年派有 原创性观察暗示KLF2在调节内皮促炎中的关键作用 活化和血栓形成功能。鉴于它在血管动态平衡中的关键作用，更好地理解 研究KLF2在内皮生物学中的作用具有重要的科学意义。此外，我们的研究 证实过氧化物酶体增殖物激活物受体α(PPARpha)激活可增加KLF2 表情。PPARpha的激活已被证明具有抗炎和抗血栓作用 通过调节关键内皮细胞基因的表达来实现其特性。在这项建议中，我们将探讨 KLF2和PPARpha之间在内皮基因表达和功能方面的新联系。然后 关键的观察结果将通过转基因小鼠的功能获得和丧失在体内得到证实 学习。所有研究都已在K99阶段开始，并将继续到Roo阶段。重要的是，这些 研究将为KLF2如何调节内皮功能提供重要的见解，并可能作为 限制/预防包括动脉粥样硬化在内的血管疾病的新治疗策略的基础。 通过Roo奖继续支持该项目将在PI中发挥关键和必要的作用 发展成为独立的调查员。私家侦查员已在 K99阶段，现在正在向NIH资助的独立网络调查员过渡。

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.