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(HIF-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 HIF-1 alpha expression and function. Specifically, our studies show that (1) KLF2 inhibits HIF-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 combination of molecular and genetic approaches will be undertaken (1) to determine the molecular basis for KLF2-mediated inhibition of HIFlalpha 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 long-term goals of translating basic mechanisms of inflammation toward the development of novel therapies. 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 immune cell biology research as an NIH-funded faculty member.
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