Pharm & NS
OBESITY AND DIABETES
Changcheng Zhou, Ph.D.
Obesity is an independent risk factor for atherosclerotic cardiovascular disease (CVD) but the mechanisms linking obesity and risk of CVD are not completely understood. Macrophages play a critical role in atherogenesis and accumulation of lipid-loaded macrophages is a hallmark or atherosclerosis. Macrophage activation and infiltration into adipose tissues is also associated with diet-induced obesity and is suspected to contribute to obesity-associated CVD. Many inflammatory pathways that contribute to atherosclerosis initiation and development are regulated by the transcriptional factor nuclear factor-kappaB (NF-κappaB), a central coordinator of the innate and adaptive immune responses. IκappaB kinase beta (IKKbeta) is the predominant catalytic subunit of the IKK complex that is required for activation of NF-κappaB in the classical activation pathway. We hypothesize that IKKbeta plays an important role in linking macrophage inflammation to atherosclerosis and that activation of IKKbeta also contributes to macrophage infiltration into adipose tissue, insulin resistance and atherosclerosis in diet-induced obesity. To test this hypothesis, we generated low density lipoprotein receptor knockout (LDLR-/-) mice lacking IKKbeta in macrophages. We will use this model to determine the role of IKKbeta in macrophage functions and the progression of atherosclerosis. We will also determine the contribution of IKKbeta activation towards high fat diet-induced obesity and atherosclerosis. The proposed studies will contribute to our understanding of the inflammatory link between obesity and atherosclerosis.
PROJECT 4 MENTORS
R. Webb, Ph.D.
Smyth, M.D., Ph.D.
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