This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Obesity is associated with several diseases. Inflammation is a common link between obesity and associated diseases. Two such diseases influencing the obese population are diabetes in the form of insulin resistance, and coronary artery disease in the form of atherosclerosis. Both of these obesity-induced complications are associated with inflammation in either the blood vessel wall (atherosclerosis) or in adipose tissue (insulin resistance). Many inflammatory pathways that contribute to atherosclerosis initiation and development are regulated by transcriptional factor nuclear factor-?B (NF-?B), a central coordinator of the innate and adaptive immune responses (8, 9). NF-?B is rapidly activated in response to various stimuli, including cytokines, infectious agents and reactive oxygen species (10). I?B kinase ? (IKK?) is the predominant catalytic subunit of the IKK complex that is required for activation of NF-?B by inflammatory mediators such as TNF? and IL-1s in the canonical or classical activation pathway (11, 12). In the past decade, IKK? has been established as a critical molecular link between inflammation and pathogenesis of several chronic diseases such as cancer. However, the role of IKK? in atherosclerosis has not been thoroughly investigated. IKK? activation has been detected in atherosclerosis and in vascular inflammatory reactions in animal models and humans (13-15). Despite the strong evidence suggesting the involvement of IKK? activation in atherosclerosis progression, the role of IKK?-mediated inflammatory functions by macrophages in atherosclerosis remain unclear. The previous studies using various mouse models have given inconsistent results and further research is urgently needed to define the role of macrophage IKK? in atherosclerosis. Preliminary data demonstrate that deficiency of IKKbeta in macrophages promotes inflammation. In addition, pilot studies indicate that deficiency of IKKbeta in macrophages reduces diet-induced atherosclerosis. We hypothesize that IKKbeta plays an important role linking macrophage inflammation to obesity-induced atherosclerosis and insulin resistance. Studies will address the role of macrophage IKKbeta in experimental models of diet-induced atherosclerosis and insulin resistance.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Exploratory Grants (P20)
Project #
5P20RR021954-04
Application #
8360251
Study Section
National Center for Research Resources Initial Review Group (RIRG)
Project Start
2011-07-01
Project End
2012-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
4
Fiscal Year
2011
Total Cost
$250,605
Indirect Cost
Name
University of Kentucky
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
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Brown, J Mark; Temel, Ryan E; Graf, Gregory A (2017) Para-bile-osis Establishes a Role for Nonbiliary Macrophage to Feces Reverse Cholesterol Transport. Arterioscler Thromb Vasc Biol 37:738-739
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Wu, Chia-Hua; Mohammadmoradi, Shayan; Thompson, Joel et al. (2016) Adipocyte (Pro)Renin-Receptor Deficiency Induces Lipodystrophy, Liver Steatosis and Increases Blood Pressure in Male Mice. Hypertension 68:213-9
Lu, Hong; Wu, Congqing; Howatt, Deborah A et al. (2016) Angiotensinogen Exerts Effects Independent of Angiotensin II. Arterioscler Thromb Vasc Biol 36:256-65
Creasy, Kate T; Jiang, Jieyun; Ren, Hui et al. (2016) Zinc Fingers and Homeoboxes 2 (Zhx2) Regulates Sexually Dimorphic Cyp Gene Expression in the Adult Mouse Liver. Gene Expr 17:7-17
Howatt, Deborah A; Balakrishnan, Anju; Moorleghen, Jessica J et al. (2016) Leukocyte Calpain Deficiency Reduces Angiotensin II-Induced Inflammation and Atherosclerosis But Not Abdominal Aortic Aneurysms in Mice. Arterioscler Thromb Vasc Biol 36:835-45

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