DTIC ADA500873: Molecular Mechanisms and Treatment Strategies pdf

DTIC ADA500873: Molecular Mechanisms and Treatment Strategies

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There is an epidemic of obesity in the military. Obesity leads to type 2 diabetes, the most dangerous consequence of which is atherothrombotic vascular disease. We have made major progress on the key Tasks over the last year. We have gained more in-depth understanding on how the AngII targets CaMKII and NADPH oxidase trigger apoptosis in ER-stressed macrophages. Our knowledge of how PPARs and obesity affect advanced plaque progression was expanded into the areas of monocyte/macrophage subsets and efferocytosis. The mechanism of obesity-associated adipokines was advanced by showing that LPS, as a model of adiponectin-LPS complex, can suppress a pro-apoptotic branch of the UPR in vivo by the exact same mechanisms elucidated in vitro. Moreover, we found that another obesity-associated adipokine-eNampt-may promote macrophage-associated disease processes in obese subjects. Finally, we showed that a specific molecular event that could promote plaque necrosis and likely occurs in obesity-cleavage of the efferocytosis receptor Mertk-occurs in advanced human plaques.

In summary, we have made substantial progress in understanding how obesity leads to accelerated heart disease at a molecular-cellular level. Further work in these areas during Year #4 is likely to suggest novel therapeutic targets to prevent obesity-associated vascular disease in military personnel and in the general public

• Creator/s: Defense Technical Information Center
• Date: 12/1/2008
• Year: 2008
• Book Topics/Themes: DTIC Archive, , COLUMBIA UNIV NEW YORK, *PROTEINS, *OBESITY, *CORONARY DISEASE, *VASCULAR DISEASES, *DIABETES, MOLECULAR PROPERTIES, HEART, ATHEROSCLEROSIS, EPIDEMIOLOGY, MACROPHAGES, CORONARY ARTERIES, MILITARY PERSONNEL, CARDIOVASCULAR DISEASES, INSULIN, IN VIVO ANALYSIS, THERAPY, IN VITRO ANALYSIS, APOPTOSIS, CLEAVAGE

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