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.

Public Health Relevance

; The factor HlF-1 promotes macrophages activation and inflammation that contributes to the pathogenesis of a number of pathologic disease states ranging from sepsis to atherosclerosis and tumor development. The applicant has identified the factor KLF2 as a novel and potent inhibitor of HIF-1 function. These studies seek to understand the detailed basis for this effect in an effort to develop novel strategies to treat inflammation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Transition Award (R00)
Project #
5R00HL097023-04
Application #
8327773
Study Section
Special Emphasis Panel (NSS)
Program Officer
Roltsch, Mark
Project Start
2011-09-06
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
4
Fiscal Year
2012
Total Cost
$249,000
Indirect Cost
$90,401
Name
Case Western Reserve University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
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Mahabeleshwar, Ganapati H; Qureshi, Muhammad Awais; Takami, Yoichi et al. (2012) A myeloid hypoxia-inducible factor 1*-Kruppel-like factor 2 pathway regulates gram-positive endotoxin-mediated sepsis. J Biol Chem 287:1448-57
Jeyaraj, Darwin; Scheer, Frank A J L; Ripperger, Jurgen A et al. (2012) Klf15 orchestrates circadian nitrogen homeostasis. Cell Metab 15:311-23