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.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Resource-Related Research Projects (R24)
Project #
5R24RR013200-03
Application #
6343928
Study Section
National Center for Research Resources Initial Review Group (RIRG)
Program Officer
Chang, Michael
Project Start
1998-12-14
Project End
2002-12-13
Budget Start
2000-12-14
Budget End
2001-12-13
Support Year
3
Fiscal Year
2001
Total Cost
$208,610
Indirect Cost
Name
University of South Alabama
Department
Pharmacology
Type
Schools of Medicine
DUNS #
City
Mobile
State
AL
Country
United States
Zip Code
36688
Vasauskas, Audrey A; Hubler, Tina R; Mahanic, Christina et al. (2011) Regulation and distribution of squirrel monkey chorionic gonadotropin and secretogranin II in the pituitary. Gen Comp Endocrinol 170:509-13
Vasauskas, Audrey A; Hubler, Tina R; Boston, Lori et al. (2011) Tissue-specific expression of squirrel monkey chorionic gonadotropin. Gen Comp Endocrinol 170:514-21
Cioffi, Donna L; Hubler, Tina R; Scammell, Jonathan G (2011) Organization and function of the FKBP52 and FKBP51 genes. Curr Opin Pharmacol 11:308-13
Gross, Katherine L; Westberry, Jenne M; Hubler, Tina R et al. (2008) Androgen resistance in squirrel monkeys (Saimiri spp.). Comp Med 58:381-8
Sadosky, Patti W; Scammell, Jonathan G (2008) Increased production of 11beta-hydroxysteroid dehydrogenase type 2 in the kidney microsomes of squirrel monkeys (Saimiri spp.). Comp Med 58:180-7
Scammell, Jonathan G; Funkhouser, Jane D; Moyer, Felricia S et al. (2008) Molecular cloning of pituitary glycoprotein alpha-subunit and follicle stimulating hormone and chorionic gonadotropin beta-subunits from New World squirrel monkey and owl monkey. Gen Comp Endocrinol 155:534-41
Schuler, A Michele; Westberry, Jenne M; Scammell, Jonathan G et al. (2006) Ovarian stimulation of squirrel monkeys (Saimiri boliviensis boliviensis) using pregnant mare serum gonadotropin. Comp Med 56:12-6
Denny, Wesley B; Prapapanich, Viravan; Smith, David F et al. (2005) Structure-function analysis of squirrel monkey FK506-binding protein 51, a potent inhibitor of glucocorticoid receptor activity. Endocrinology 146:3194-201
Gross, Katherine L; Cioffi, Eugene A; Scammell, Jonathan G (2004) Increased activity of the calcineurin-nuclear factor of activated T cells pathway in squirrel monkey B-Lymphoblasts identified by PowerBlot. In Vitro Cell Dev Biol Anim 40:57-63
Sinars, Cindy R; Cheung-Flynn, Joyce; Rimerman, Ronald A et al. (2003) Structure of the large FK506-binding protein FKBP51, an Hsp90-binding protein and a component of steroid receptor complexes. Proc Natl Acad Sci U S A 100:868-73

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