The Role of Glucocorticoids in Cell Fate Determination

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DESCRIPTION (provided by applicant): The goal of this research is to investigate how glucocorticoids (GCs) regulate the differentiation of pluripotent cells into adipocytes and the role of myostatin, a GC regulated gene, in directing this process. The long term objectives are to understand how GCs, acting via their receptor (GR), influence cell fate determination and differentiation. GCs have been used to therapeutically induce differentiation of a broad range of cell types including premature lung tissue in the fetus and immature malignancies such as leukemia and neuroblastoma. GCs have also been used as therapy for a wide range of medical conditions including transplant rejection, asthma, rheumatoid arthritis and other autoimmune diseases. Interestingly, the side effects of GC excess have a signifcant overlap with the signs and symptoms of insulin resistance and the metabolic syndrome. However, a direct connection between GC activity and the development of the metabolic syndrome has yet to be elucidated. The aim of this study study is to examine the hypothesis that the same pathways involved in GC regulation of cell fate determination and differentiation programs may contribute to the development of some of the side effects found in patients with GC excess such as obesity and insulin resistance. The overall goal is to understand how GCs regulate cell fate and the role this pathway plays in both physiology and disease. This project will focus on the regulation of a GC target gene (myostatin) and the implications of this regulation on: cell fate determination, adipogenesis and insulin sensitivity. There are three specific aims: (1) to investigate the regulation of myostatin by GCs in pluripotent mesenchymal cells in order to assess the effect on cell fate determination, (2) to analyze of the role of GR and myostatin in adipogenesis in vivo, and (3) to evaluate the role of GR in adipocyte differentiation and in the pathophysiological changes in GC related diseases and determine if myostatin is relevant to GR's role in these diseases. This project will use molecular biology techniques and genetically modified mouse models, including transgenics and knock-outs, to elucidate the mechanisms by which GCs regulate myostatin with a focus on adipocyte cell fate. This research will provide insight into the cause of the debilitating side effects of GC therapy that millions of people suffer from. In addition, it will shed light on the mechanisms of GC action which has important implications for understanding the development of diseases such as diabetes.