Aging is associated with immune system dysfunction and increases the risk of cardiovascular disease. Our past studies have examined the mechanisms controlling apoptosis and the disposal of cell corpses in cardiovascular tissues. During the past funding period we developed a mouse model of autoimmunity and accelerated atherosclerosis. Analysis of this new mouse line demonstrated that impaired clearance of apoptotic cells was a critical determinant of both vascular lesion formation and the autoimmune phenotype. Because obesity accelerates the incidence of numerous age-related diseases, including atherosclerosis and immune dysfunction, our recent studies have explored the molecular links between adipose tissue and apoptotic cell clearance. This research has led to the recent discovery that the adipocyte-derived protein adiponectin functions in the clearance of apoptotic cells. Adiponectin is a circulating protein that is abundantly expressed in healthy lean individual, but levels decline as body mass increases. These findings have led us to speculate that premature immune system dysfunction will occur in hypo-adiponectinemic organisms, leading to the inefficient disposal of apoptotic cells. The proposed research will test the hypothesis that clearance of apoptotic cells is impaired by adiponectin-deficiency. We will also analyze the related hypothesis that apoptotic corpses accumulate in elderly organisms, contributing to autoimmunity and chronic inflammatory states that promote age-related diseases. To accomplish these aims we will: 1. Analyze age-dependent changes in apoptotic cell clearance in novel mouse genetic models involving adiponectin-deficiency. 2. Perform cellular analyses of apoptotic cell clearance to define the mechanism of adiponectin action. 3. Analyze the role of adiponectin-deficiency in the age-dependent decline of lung function.
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