Monkeys of South and Central American origin (New World primates) are resistant to the cellular actions of steroid hormones produced by the adrenal gland and the gonads, and to the vitamin D prohormone 25-hydroxyvitamin D, and hormone 1,25-dihydroxyvitamin D. A compensatory increase in hormone production accommodates the requirement for increased circulating levels of the steroid hormones, while substantial environmental sunlight exposure, as occurs in the canopy of the Amazon rain forest, is needed to maintain adequate vitamin D substrate for vitamin D hormone synthesis in New World primates. Failure to meet their requirements for cutaneous vitamin photoproduction leads to relative vitamin D deficiency and a morbid clinical syndrome characterized by skeletal fragility and deformity accompanied by extreme muscle weakness. The applicants' investigation of an outbreak of rickets in a New World primate colony at the Los Angles Zoo revealed the cellular basis for resistance. Cultured cells from primates in all hormone-resistant genera over-expressed two novel classes of intracellular proteins (one a hormone binding chaperone-like protein in the cytoplasm of the cell; the second, a single-strand, hormone response element DNA binding protein in the nucleus), which interrupt sterol/steroid hormone signal transduction independent of receptor proteins for the hormone.
The Specific Aims of the current renewal application are the molecular cloning, and expression of these two novel categories of proteins to determine why and how they legislate receptor-independent, sterol/steroid hormone resistance in New World primate cells. This will be achieved by the application of state-of-the-art technology in (1) chromatographic purification of sterols; (2) affinity-purification of cellular proteins; and (3) cDNA cloning and regulated expression of the vitamin D-resistance -causing proteins on a wild-type background. Although constitutively over-expressed in New World primates, there are counterparts for these proteins in Old World primates, including man. Hence, the ultimate aim of this research program is to employ Nature's successful transgenic experiment with New World monkeys to [1] understand the roles of these dominant-negative-acting proteins in normal human cellular biochemistry and physiology; and [2] determine if tissue-specific expression of these proteins is of pharmacological benefit in human disease, where up-and down-regulation of steroid hormone action is of clinical benefit.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Orthopedics and Musculoskeletal Study Section (ORTH)
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Sharrock, William J
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Cedars-Sinai Medical Center
Los Angeles
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Zhou, Rui; Chun, Rene F; Lisse, Thomas S et al. (2015) Vitamin D and alternative splicing of RNA. J Steroid Biochem Mol Biol 148:310-7
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Chen, Hong; Gilbert, Linda C; Lu, X et al. (2011) A new regulator of osteoclastogenesis: estrogen response element-binding protein in bone. J Bone Miner Res 26:2537-47
Hewison, Martin; Adams, John S (2010) Vitamin D insufficiency and skeletal development in utero. J Bone Miner Res 25:11-3

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