ANIMAL MODEL OF GLUCOCORTICOID RESISTANCE

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Glucocorticoid resistance, defined as a diminished state of sensitivity to glucocorticoids, is observed in a number of human disease states including cancer, asthma, AIDS and rheumatoid arthritis. Glucocorticoid resistance may be generalized or tissue-specific and may profoundly influence response to therapeutic intervention. Glucocorticoid resistance likely occurs at multiple steps in the glucocorticoid response pathway although the molecular details are largely lacking. There have been no animal models of glucocorticoid resistance to gain new insight into possible mechanisms. The long-term goal of this project is to understand the molecular basis for glucocorticoid sensitivity in the squirrel monkey, a neotropical primate with naturally occurring glucocorticoid resistance. We hypothesize that glucocorticoid resistance in the squirrel monkey results from the relative overexpression of the immunophilin FKBP51 which associates with the glucocorticoid receptor heterocomplex leading to low binding affinity. Until now, none of the immunophilins had not been thought to influence glucocorticoid receptor binding. As FKBP51 is upregulated by glucocorticoids this may represent a short-feedback loop to moderate the sensitivity of a tissue upon continued exposure to the hormone. Thus, our preliminary studies in the squirrel monkey have uncovered a novel mechanism for regulating glucocorticoid sensitivity, a finding with potentially broad implications to understanding glucocorticoid resistance in human disease. The experiments outlined in this proposal will focus on: (1) the role of differential expression of the receptor associated-immunophilins FKBP51 and FKBP52 on the binding affinity of in vitro transcribed-translated glucocorticoid receptor and of endogenous glucocorticoid receptors in squirrel monkey and human lymphocytes; (2) the molecular basis for increased expression of FKBP51 in squirrel monkey cells. In so doing, we will generate squirrel monkey cell lines, squirrel monkey cDNA and genomic libraries, cDNA probes, and antibodies to squirrel monkey-specific proteins which will be made available to other investigators through the Squirrel Monkey Breeding and Research Resource.