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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Career Transition Award (K99)
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Special Emphasis Panel (ZHL1-CSR-Z (M3))
Program Officer
Commarato, Michael
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Case Western Reserve University
Internal Medicine/Medicine
Schools of Medicine
United States
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Goodman, W A; Omenetti, S; Date, D et al. (2016) KLF6 contributes to myeloid cell plasticity in the pathogenesis of intestinal inflammation. Mucosal Immunol 9:1250-62
Date, Dipali; Das, Riku; Narla, Goutham et al. (2014) Kruppel-like transcription factor 6 regulates inflammatory macrophage polarization. J Biol Chem 289:10318-29
Sharma, Nikunj; Lu, Yuan; Zhou, Guangjin et al. (2012) Myeloid Krüppel-like factor 4 deficiency augments atherogenesis in ApoE-/- mice--brief report. Arterioscler Thromb Vasc Biol 32:2836-8
Jeyaraj, Darwin; Scheer, Frank A J L; Ripperger, Jürgen A et al. (2012) Klf15 orchestrates circadian nitrogen homeostasis. Cell Metab 15:311-23
Mahabeleshwar, Ganapati H; Qureshi, Muhammad Awais; Takami, Yoichi et al. (2012) A myeloid hypoxia-inducible factor 1?-Krüppel-like factor 2 pathway regulates gram-positive endotoxin-mediated sepsis. J Biol Chem 287:1448-57
Mahabeleshwar, Ganapati H; Kawanami, Daiji; Sharma, Nikunj et al. (2011) The myeloid transcription factor KLF2 regulates the host response to polymicrobial infection and endotoxic shock. Immunity 34:715-28
Liao, Xudong; Sharma, Nikunj; Kapadia, Fehmida et al. (2011) Kruppel-like factor 4 regulates macrophage polarization. J Clin Invest 121:2736-49
Lin, Zhiyong; Natesan, Viswanath; Shi, Hong et al. (2010) Kruppel-like factor 2 regulates endothelial barrier function. Arterioscler Thromb Vasc Biol 30:1952-9