Grant: Project Grant

Metabolic disorders are a huge and growing clinical and financial burden in the world. Economic progress has generated a global epidemic in obesity that is in turn producing an epidemic of diabetes along with its long-term complications of cardiovascular diseases, renal failure, blindness, cancer and dementia. Medical progress has converted many previous life threatening diseases into chronic disorders. These chronic disorders (e.g. congestive heart failure, COPD, kidney insufficiency, diabetes, HIV, some forms of cancer) are often complicated by muscle atrophy which leads to weakness, impaired physical function and decreased survival. My laboratory has been exploring the role of the ubiquitin system in metabolism. The ubiquitin system functions in cells by regulating in a precise manner, the degradation of specific proteins in the cell. We have found an enzyme in the ubiquitin system called USP19 that when inactivated in mice protects them from obesity and diabetes on a high fat diet as well as from muscle wasting due to many catabolic conditions such as nutritional insufficiency, glucocorticoid treatment and muscular inactivity. In this project, we propose to understand at a molecular level how USP19 exerts these functions in order to better direct drug development on this enzyme which is currently underway.