KLF2 Mediated HIF-1 Regulation and Macrophage Activation

炎症反应在调节广泛的生理和病理状态中是至关重要的。 组织巨噬细胞是这种反应的中心调节器-从炎症的开始到消退。 最近的研究已经确定缺氧诱导因子1 α（HIF-1 α）作为缺氧诱导因子1 α（HIF-1 α）的关键调节因子。 巨噬细胞活化功能使用功能增益和功能丧失方法的组合，PI 将KLF 2鉴定为HIF-1 α表达和功能的新内源性调节剂。具体来说，我们 研究表明：（1）KLF 2抑制H1 F-1的表达和转录活性;（2）改变KLF 2 表达影响HIF-1 α靶基因表达、ATP产生、细胞因子/MMP表达， 巨噬细胞的细菌/杀肿瘤活性。在这个建议中，分子和遗传学的结合 方法将采取（1），以确定KLF 2介导的抑制的分子基础， HIF-1 α表达，（2）评估改变KLF 2水平对缺氧或LPS介导的HIF-1 α表达的影响。 活化巨噬细胞，和（3）评估改变KLF 2水平对缺氧或LPS介导的 体内巨噬细胞功能。这些研究将为申请人实现其长期目标奠定基础 目标是将炎症的基本机制转化为新疗法的发展。 通过ROO奖继续支持这个项目将在Pi的 发展成为独立调查员。PI已完成必要的额外培训 K99阶段的奖励，现在正在过渡成为一个NIH资助的独立调查员， 充分的体制支持。

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.