"Metabolic Syndrome, Inflammation, and Vascular Remodeling" is the central theme of this SCCOR. Inflammation is increasingly accepted as a major contributor to the pathogenesis of coronary heart disease (CHD) and type 2 diabetes. Insulin resistance and the metabolic syndrome appear to be at the root of the pathogenic process. In this SCCOR grant we have united important new discoveries in diverse areas of research to determine whether primary targeting of inflammation as a therapeutic goal provides a new route to treat CHD. We will target inflammation via lifestyle intervention, indirectly using PPARa agonists, and directly by inhibiting the NF-KB pathway, the master switch of inflammation. We will combine these novel series of interventions with a newly developing, state-of-the-art, minimally invasive imaging technique, multidetector computed tomographic angiography (MDCTA) that examines dynamic processes in the coronary circulation, including the development and regression of soft and hard plaques.
Specific Aims i nclude: Project by Shoelson: To determine how obesity- and Western diet-induced inflammation influences CHD in animal models. We have discovered that obesity activates a subacute inflammatory process in fat and liver via NF-KB, which leads to the production of cytokines and causes systemic insulin resistance. We have hypothesized that the obesity-driven production of these cytokines promotes CHD and will test this in relevant rodent models. In a series of three clinical projects we will use different interventions to target subacute inflammation in patients with established CHD and assess the effect of the interventions on regression of soft plaque assessed by MDCTA. Project by Welty: Since Western diet and obesity activate the NF-KB cascade, we hypothesize that weight loss achieved through dietary and exercise intervention will suppress the subacute inflammatory process to promote vascular remodeling and regression of soft plaque, and in Project by Goldfarb: We will directly target the inflammatory signaling

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center (P50)
Project #
5P50HL083813-05
Application #
8306698
Study Section
Special Emphasis Panel (ZHL1-CSR-A (F1))
Program Officer
Mcdonald, Cheryl
Project Start
2006-05-01
Project End
2014-04-30
Budget Start
2012-08-06
Budget End
2014-04-30
Support Year
5
Fiscal Year
2012
Total Cost
$2,830,751
Indirect Cost
$413,629
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
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