Diabetes mellitus type-2 (DM-2) is increasing in prevalence in the US and throughout the developing world, and its rise parallels an increase in obesity. The pathophysiology connecting the conditions is yet to be elucidated but appears to involve a dysregulation between pro- and anti-inflammatory pathways. The long-term sequelae of DM-2 and obesity include abnormal lipid profiles, hypertension, and cardiovascular disease, together known as the metabolic syndrome. Adipose tissue, long known to have a primary role in the storage of fat, is also regarded as an endocrine tissue that actively regulates metabolism and inflammation. Protein hormones secreted by adipocytes (adipokines) are likely necessary for these regulatory pathways and may represent therapeutic targets for DM-2, obesity, and cardiovascular disease. One adipokine, Acrip30/Adiponectin, plays a central role in the link between adipose and peripheral tissues. Acrp30's mode of action is not fully understood but involves signaling pathways activated by specific oligomeric isoforms and proteolytic fragments of the molecule that bind cell-surface receptors and alter gene expression and metabolism. T-cadherin, an endothelial cell adhesion molecule, was identified as a cell-surface receptor for Acrp30. Preliminary results indicate mice lacking T-cadherin are diabetic. The specific experimental goals of this proposal are as follows: 1) identify the functional species of Acrp30 that binds T-cadherin, 2) map the functional domains of the receptor-ligand interaction and develop a molecular model of this interaction, and 3) characterize the signaling and regulatory pathways of this receptor and ligand. This work may suggest new insights into the development and treatment of cardiovascular disease and obesity associated with DM-2, a leading cause of morbidity and mortality in the United States. As part of this proposal, and working with the basic science sponsors, the applicant will receive training in molecular and cellular biology in order to gain the requisite skills and knowledge to become an independent investigator.
