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: 8505528
• 负责人: Ganapati Holanagadde Mahabaleshwar
• 金额: $ 23.7万
• 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 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8505528
• 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.

炎症反应对于调节广泛的生理和病理状态至关重要。 组织巨噬细胞是该反应的中心调节因子 - 从启动到分辨率O炎症。 最近的研究已经确定缺氧诱导因子1Alpha（HLF-1α）是关键调节剂 巨噬细胞激活函数。使用功能和功能丧失方法的结合，PI具有 将KLF2鉴定为HLF-1α表达和功能的新型内源调节剂。具体来说，我们的 研究表明，（1）KLF2抑制了HLF-1的表达和转录活性。 （2）更改KLF2 表达会影响HIF-LALPHA靶基因表达，ATP产生，细胞因子/MMP表达和 巨噬细胞的细菌/肿瘤活性。在此提案中，分子和遗传 将采取方法（1）确定KLF2介导的抑制的分子基础 HIF-Lalpha表达，（2）评估改变KLF2水平对缺氧或LPS介导的影响的影响 巨噬细胞的激活，（3）评估改变KLF2水平对缺氧或LPS介导的影响的影响 体内巨噬细胞功能。这些研究将为申请人实现长期的基础 将炎症的基本机制转化为新疗法发展的目标。 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。 PL在此期间完成了必要的额外培训 K99奖励阶段，现在正朝着成为NIH资助的独立调查员的转变 足够的机构支持。