Functional Dissection of Glucocorticoid Action in Metabolic Disease

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DESCRIPTION (provided by applicant): Dr. Charles Harris is an MD/PhD trained endocrinologist with a strong interest in metabolism. Dr. Harris's development as a physician scientist was nurtured as a trainee in Washington University's Medical Scientist Training Program. His interest in glucocorticoids (GCs) was sparked as a clinical endocrine fellow seeing patients with Cushing's disease, a state of GC excess. These patients suffer from central obesity, diabetes, hypertension, osteoporosis, and CNS changes. Metabolic syndrome (MS) may also be the result of excess GC signaling, but restricted to adipose tissue. The long-term goals of Dr. Harris's work is to understand the molecular mechanisms for these effects of GCs on adipose, muscle, liver, bone and brain. GCs bind to the glucocorticoid receptor (GR). GR, a nuclear hormone receptor, activates transcription of a number of genes with GRE regulatory elements. In addition, GR inhibits transcription by tethering transcriptional complexes such as AP-1 and NF-kB. A particular mutation of GR, GRdim is of interest because transactivation is lost for the majority of target genes. A minority of GR targets are still activated by GRdim pointing to a minor subset of GR dimerization-independent target genes. Dr. Harris will dissect the metabolic effects of GCs in vitro and in vivo using cells and mice harboring the GR mutation, GRdim. In this manner he will be able to determine the physiological significance of the GR dimerization-dependent targets. In addition, Dr. Harris will further address the role of GR action in adipose tissue by creating an adipose-specific GR null mouse. Aim 1: To identify the mechanisms of glucocorticoid-mediated adipogenesis and insulin resistance in adipocytes. Aim 2: To determine if the metabolic derangements induced by excess glucocorticoids are mediated by GR dimerization-dependent targets or by GR action in adipose tissue. Aim 3: To determine if the obesogenic properties of a high-fat diet are mediated by GR dimerization-dependent targets and if they are mediated by GR action in adipose tissue. By completing these aims Dr. Harris will make his transition to becoming an independent physician-scientist researcher in academic medicine, his career goal. Relevance: The research will shed light on the etiology of GC-mediated adverse metabolic effects as well as the metabolic syndrome. In addition, the proposed research could point to the use of "dissociated GCs", safer anti-inflammatory medications to treat the millions of patients afflicted with inflammatory diseases.