KLF2, PPARalpha and Atherothrombosis

描述(由申请人提供)： 这项建议描述了一项旨在阐明转录因子KLF2在维持血管内稳态中的作用的研究计划。在美国，心血管疾病是主要的死亡原因。血管内皮细胞构成了血液和身体其他组织之间的界面，在健康和疾病中发挥着基础性的作用。内皮功能障碍是多种心血管疾病发生发展过程中的重要病理生理事件。这位候选人做出了独到的观察，暗示了KLF2在调节内皮细胞促炎活性和血栓形成功能中的关键作用。鉴于KLF2在血管内稳态中的关键作用，更好地了解KLF2在内皮生物学中的功能具有重要的科学意义。在这项提议中，特定的目标1被设计来描述KLF2的S在基础和层流条件下调节血栓调节蛋白的分子基础。此外，我们的研究表明，激活过氧化物酶体增殖物激活物受体α(PPARpha)会增加KLF2的表达。PPARpha的激活已被证明通过调节关键的内皮基因的表达而显示出抗炎和抗血栓的特性。在特定的目标2中，我们将在内皮基因表达和功能的背景下探索KLF2和PPARpha之间的这种新的联系。在具体目标3中，将通过功能获得和丧失研究，使用转基因小鼠在体内证实关键观察结果。所有研究将在指导阶段开始，并将继续进入独立阶段。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K99/R00奖支持这一项目将在候选人成为独立调查员的过程中发挥关键和必要的作用。他的直接目标是通过额外的密集指导、技术培训和广泛的智力发展来巩固他的研究经验，这将直接产生于这项提议。高度结构化的职业发展计划是这项建议的内在组成部分，旨在极大地提高候选人长期职业目标的实现：作为NIH资助的教员，独立完成血管生物学研究。

DESCRIPTION (provided by applicant): 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.