Amy J. Wagers, Ph.D.,
Assistant Professor of Pathology Section on Developmental and Stem Cell Biology, Joslin Diabetes Center
Work in the Wagers lab focuses on understanding the mechanisms that regulate the function of blood-forming and muscle-forming stem cells. Of particular interest are factors and mechanisms that determine the self-renewal, differentiation, and migratory potentials of these stem cells. We have established highly sensitive methods to quantitatively assess stem cell function and to distinguish local and systemic effects on these cells that impact their effectiveness in tissue repair. Using these approaches, we are defining novel intrinsic and extrinsic regulators of stem cell function that may promote normal tissue maintenance, and therefore be targeted to prevent degenerative pathologies associated with disease and aging.

Anders M. Näär, Ph.D.
Assistant Professor of Cell Biology, Harvard Medical School and Massachusetts General Hospital Cancer Center
Our research is focused on elucidating molecular mechanisms of gene regulation, with particular emphasis on the action of transcription regulators involved in aging-associated diseases (e.g. metabolic syndrome, a constellation of diseases and conditions including obesity, insulin resistance, elevated LDL/HDL ratio, hypertriglyceridemia, hypertension, and hepatosteatosis, which are linked to cardiovascular disease and type II diabetes). Changes in energy metabolism and cholesterol/lipid homeostasis have been suggested as important risk factors for the development of aging-related diseases and conditions associated with metabolic syndrome. Moreover, Alzheimers Disease (AD) is connected with cholesterol trafficking (e.g. ApoE4), and cholesterol and statins modulate amyloid precursor protein (APP) processing in cultured cells and animal models. A number of cancers, including prostate and breast cancer, are also associated with increased dietary fat intake and obesity. There is clearly an urgent need for improved understanding of the molecular mechanisms governing energy and lipid/cholesterol homeostasis to facilitate the elucidation of aging mechanisms and for the development of new treatment modalities to combat the rise in aging-associated diseases. We have investigated the functions of the sterol regulatory element binding protein (SREBP) family of transcription factors, which are key regulators of genes involved in lipid and cholesterol homeostasis. Our studies revealed that SREBPs stimulate expression of genes by recruiting co-activators, such as the histone acetyltransferases CBP/p300 and the RNA polymerase II-binding ARC/Mediator. Moreover, we have found that the activation domain of SREBPs can interact with the activator-targeted KIX domains present in CBP/p300 and the ARC/Mediator subunit ARC105 (also known as MED15). This detailed understanding of the mechanism by which SREBPs regulate cholesterol and lipid biosynthesis and trafficking has facilitated ongoing efforts to identify small molecule-inhibitors of SREBPs that could ultimately provide novel therapeutic strategies for the treatment of metabolic syndrome. Our future research directions also include studying the mechanisms by which SREBPs are normally inactivated in response to fasting/starvation, and we have recently found intriguing functional connections with the sirtuin pathway linked to the anti-aging effects of caloric restriction. These preliminary findings suggest that SREBPs might serve as physiologically important targets of the anti-aging action of sirtuins in metazoans.