The metabolic syndrome (MetS) is a constellation of biochemical and physical derangements that afflicts nearly 20-25% of individuals worldwide. Key features of MetS include the concurrence of obesity, insulin resistance (IR), dyslipidemia, hypertension, and a pro-inflammatory state. It is increasingly appreciated that chronic inflammation is a unifying underlying mechanism not only for the development of MetS but also for the subsequent development of atherosclerotic cardiovascular disease - the primary source of morbidity and mortality in these individuals. Whereas the molecular mechanisms governing the inception and progression of MetS are undoubtedly complex, there is an increasing appreciation that derangements of the innate immune system are central to the loss of systemic metabolic coordination. Specifically, recent studies highlight an essential role for cells of the monocyte/macrophage lineage in the development of both MetS and its cardiovascular consequences. Kruppel-like factors (KLFs) are zinc-finger transcription factors implicated in a wide spectrum of biological processes including hematopoiesis. Our group provided the initial link implicating KLF2 in myeloid cell biology, and under the auspices of this grant, identified KLF2 as an endogenous repressor of proinflammatory macrophage activation. Specifically, KLF2 was shown to regulate two ancient stress pathways central to activation of the innate immune system in the setting of inflammation and hypoxia, namely NFkB and HIF-1a. Further, we found that exposure of macrophages to hypoxia and/or bacterial products reduced KLF2 expression while inducing HIF-1a, findings recapitulated in human sepsis patients. Nascent observations that form the basis for this competitive renewal now identify myeloid KLF2 as critical regulator of chronic inflammatory states such as obesity and atherosclerosis. Further, our studies link KLF2 to the action of clinically relevant anti-inflammatory agents such as omega-3 fatty acids (w-3 FAs). These observations provide the foundation for the central hypothesis that myeloid KLF2 is an essential regulator of chronic inflammation. To better understand the precise role of KLF2 in macrophage biology, three aims are proposed.
In Aim 1, we will determine the molecular basis for KLF2's ability to regulate the NFkB/HIF-1 pathways.
In Aim 2, we will determine the effect of altered myeloid KLF2 expression on obesity/insulin resistance and atherogenesis. And finally, in Aim 3, we will elucidate the molecular mechanisms by which w-3 FAs induce KLF2 expression, and to determine whether the anti-inflammatory effects of these agents is KLF2-dependent. Collectively, these studies will elucidate the molecular basis for KLF2-mediated myeloid activation and the functional consequences of KLF2 sufficiency and deficiency on insulin resistance and atherogenesis. The results of these studies may also provide the foundation for novel therapies directed at the treatment of a broad spectrum of chronic inflammatory disorders.

Public Health Relevance

The macrophage is a critical regulator of the body's response to inflammation that contributes to disease processes such as insulin resistant states and atherogenesis. Recent studies from our group have identified a genetic factor that regulates macrophage activation in the setting of inflammation. In addition, we have found that this factor is regulated by omega-3 fatty acids, lipid products known to confer beneficial effects for the cardiovascular system. This proposal seeks to understand the mechanisms underlying the function of this factor with the goal of developing novel therapies for the treatment of chronic inflammatory disease states.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL086548-06
Application #
8435721
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Fleg, Jerome
Project Start
2006-12-01
Project End
2018-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
6
Fiscal Year
2013
Total Cost
$406,522
Indirect Cost
$149,026
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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