AN ANIMAL MODEL OF GLUCOCORTICOID RESISTANCE

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DESCRIPTION (Provided by applicant): This is a competing renewal of a resource-related (R24) grant, which studies the squirrel monkey as an animal model of glucocorticoid resistance in humans. In the previous grant period, the investigators demonstrated that glucocorticoid resistance in squirrel monkeys results from over expression of a potent form of the glucocorticoid receptor-associated cochaperone FKBP51. This finding has uncovered a novel function of this FK506-binding immunophilin, which results in a dramatic physiological phenotype and represents a previously unrecognized mechanism by which steroid hormone responsiveness is regulated. FKBP51, FKBP52, and cyclophilin 40 make up the large molecular immunophilins, a relatively newly discovered class of proteins, which exhibit widespread distribution. Furthermore, preliminary studies indicate these proteins have diverse effects on endocrine, immune, cardiovascular and neuronal function, growth, and development, and cancer progression. The expression of a potent form of FKBP51 in squirrel monkeys offers an "experiment of nature" to design studies of interest to investigators in multiple disciplines. The goal of the studies described here is to perform a detailed functional analysis of FKBP51 by answering the following questions: 1) Which functional domains and specific amino acid residues of squirrel monkey FKBP51 are responsible for its potent inhibitory activity on glucocorticoid receptor binding activity (Specific Aim 1)? 2) How are the human FKBP51 and human FKBP52 genes regulated in a tissue-specific and hormone/stress-dependent manner (Specific Aim 2)? 3) What are the biochemical and physiological effects of expressing squirrel monkey FKBP51 in human cells and transgenic mice (Specific Aim 3)? During the course of these studies, the investigators will continue to develop and characterize experimental materials relevant to squirrel monkey biology, which will be made available to other investigators through the Tissue and Biological Fluids Bank of the Squirrel Monkey Breeding and Research Resource (Specific Aim 4). In summary, these studies will provide important insight into the physiological role of FKBP51 while at the same time adding substantial value to the Squirrel Monkey Resource at the University of South Alabama.