Physiological Roles of Receptor-Associated Immunophilins

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DESCRIPTION (provided by applicant): The goals of this project are to understand roles of the steroid hormone receptor-associated immunophilins (FKBP51 and FKBP52) in glucocorticoid receptor (GR)-mediated physiological processes, and to assess the likelihood that the FKBP51 and FKBP52 null mice could serve as model systems for the study of known human diseases associated with altered glucocorticoid responses. First, the FKBP51 and FKBP52 gene expression patterns will be assessed in mice using various histochemical and immunohistochemical staining methods. Next, an altered GR response in mice lacking the FKBP51 and/or FKBP52 genes will be demonstrated as assessed by GR ligand binding and GR-mediated gene expression in hepatocytes isolated from FKBP51 and FKBP52 null mice. Finally, various physiological parameters that are typically altered in response to hypo- and/or hypercortisolism (e.g. truncal obesity) will be assessed in FKBP51 and FKBP52 null mice. FKBP51 overexpression has been attributed to cortisol resistance in squirrel monkeys. Thus, these studies could also contribute drugs to a better understanding of the mechanism by which patients acquire resistance to corticosteroid drugs.