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.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Resource-Related Research Projects (R24)
Project #
5R24RR013200-07
Application #
6876560
Study Section
National Center for Research Resources Initial Review Group (RIRG)
Program Officer
Harding, John D
Project Start
2003-04-01
Project End
2008-03-31
Budget Start
2005-04-01
Budget End
2006-03-31
Support Year
7
Fiscal Year
2005
Total Cost
$255,500
Indirect Cost
Name
University of South Alabama
Department
Pharmacology
Type
Schools of Medicine
DUNS #
172750234
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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