KLF2 Mediated HIF-1 Regulation and Macrophage Activation

KLF2 介导的 HIF-1 调节和巨噬细胞激活

• 批准号: 8327773
• 负责人: Ganapati Holanagadde Mahabaleshwar
• 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: 2011
• 资助国家: 美国
• 起止时间: 2011-09-06 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8327773
• 关键词: Affect; Atherosclerosis; Award; Development; Disease; Foundations; Funding; Gene Expression; Goals; Hypoxia; Hypoxia Inducible Factor; Inflammation; Inflammatory Response; Instruction; Macrophage Activation; Matrix Metalloproteinases; Mediating; Molecular; Molecular Genetics; Pathogenesis; Pathologic; Phase; Physiological; Play; Production; Regulation; Research Personnel; Resolution; Role; Sepsis; Tissues; Training; Translating; United States National Institutes of Health; base; cytokine; in vivo; inhibitor/antagonist; loss of function; macrophage; novel; novel strategies; response; tumor

The inflammatory response is critical in regulating a broad spectrum of physiologic and pathologic states. The tissue macrophage is a central regulator of this response - from initiation to resolution o inflammation. Recent studies have identified Hypoxia-inducible Factor 1alpha(HlF-1 alpha) as a key regulator of macrophage activation function. Using a combination of gain- and loss-of-function approaches, the PI has identified KLF2 as a novel endogenous regulator of HlF-1 alpha expression and function. Specifically, our studies show that (1) KLF2 inhibits HlF-1 expression and transcriptional activity; (2) altering KLF2 expression affects HIF-lalpha target gene expression, ATP production, cytokine/MMP expression, and bacterial/tumoricidal activity of macrophages. In this proposal a cornbination of molecular and genetic approaches will be undertaken (1) to determine the molecular basis for KLF2-mediated inhibition of HIF-lalpha expression, (2) to evaluate the effect of altering KLF2 levels on hypoxia or LPS mediated activation of macrophages, and (3) to assess the effect of altering KLF2 levels on hypoxia or LPS-mediated macrophage function in vivo. These studies will provide the foundation for the applicant to achieve his longterm goals of translating basic mechanisms of inflammation toward the development of novel therapies. 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 Pl has completed requisite additional training during the K99 phase of award and is now transiting toward becoming an NIH-funded independent investigator with adequate institutional support.

炎症反应在调节多种生理和病理状态方面起着关键作用。 组织巨噬细胞是这种反应的中心调节器--从启动到消退炎症。 最近的研究发现，低氧诱导因子1α(HLF-1α)是一种关键的调节因子。 巨噬细胞激活功能。结合使用增益和损失函数的方法，PI具有 KLF2是一种新的HLF-1α表达和功能的内源性调节因子。具体地说，我们的 研究表明：(1)KLF2抑制HLF-1的表达和转录活性；(2)改变KLF2 表达影响HIF-α靶基因表达、ATP产生、细胞因子/基质金属蛋白酶表达，以及 巨噬细胞的杀菌/杀瘤活性。在这项建议中，分子和遗传的结合 将采取以下方法：(1)确定KLF2介导抑制KLF2的分子基础 HIF-α的表达，(2)评价KLF2水平改变对缺氧或内毒素介导的影响 巨噬细胞的激活，以及(3)评估改变KLF2水平对缺氧或内毒素介导的影响 巨噬细胞在体内的功能。这些研究将为申请人实现其长期目标奠定基础。 将炎症的基本机制转化为新疗法的开发的目标。 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。在此期间，公共部门已完成必要的额外培训。 K99阶段的奖励，现在正在过渡到成为NIH资助的独立调查员 有足够的制度支持。