KLF2, PPARalpha and Atherothrombosis

KLF2、PPARα 和动脉粥样硬化血栓形成

• 批准号: 8102461
• 负责人: Zhiyong Lin
• 金额: $ 24.9万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8102461
• 关键词: PPAR alpha; atherothrombosis; PPAR alpha; atherothrombosis

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.

该建议描述了旨在阐明转录因子之间的交集的研究计划 KLF2和PPARALPHA维持血管稳态。心血管疾病是 在美国死亡。血管内皮，包括血液与血液之间的接口 人体的其他组织在健康和疾病中起着基本作用。内皮功能障碍是关键 多种心血管疾病的发展和发展中的病理生理事件。 Pi具有 做出了原始观察，暗示了KLF2在调节内皮促炎性中的关键作用 激活和血栓功能。鉴于其在血管稳态中的关键作用，有了更大的理解 KLF2在内皮生物学中的功能具有很大的科学利益。此外，我们的研究 表达过多的激活过氧化物酶体增殖物激活剂受体α（Pparalpha）增加了KLF2 表达。已显示p帕拉法激活表现出抗炎和抗栓性 通过调节临界内皮基因的表达的性质。在此提案中，我们将探索 在内皮基因表达和功能的背景下，KLF2和Pparalpha之间的新型联系。然后 通过获得和丧失功能的损失，将使用转基因的小鼠在体内确认关键观察结果 研究。所有研究都始于K99阶段，并将持续到ROO阶段。重要的是，这些 研究将提供有关KLF2如何调节内皮功能的重要见解，并且也可以作为 限制/预防血管疾病（包括动脉粥样硬化）的新型治疗策略的基础。 通过ROO奖对该项目的持续支持将在PI的PI中扮演关键和必要的角色 发展成为独立研究者。 PI在此期间完成了必要的额外培训 K99阶段，现在正过渡到成为NIH资助的独立研究员。