The proposed studies are designed to characterize the properties and behavior of a gonadotropin-responsive steroidogenesis activator peptide in the rat ovary and testis. This cycloheximide-sensitive factor (the putative """"""""labile protein"""""""") is comparable or identical to a similar peptide, previously isolated from the rat adrenal cortex, which activates the mitochondrial side-chain cleavage of cholesterol in a cAMP-dependent manner. To achieve the objective, the following systems will be used as appropriate, dispersed, purified normal rat Leydig cells; implanted H-540 rat Leydig cell tumors; dispersed rat luteal cells; and expressed rat preovulatory granulosa cells. The sequence of the activator peptide will be determined and a radioimmunoassay for detection and quantitation will be developed. This will permit the assessment of time- and concentration-dependent changes in the intracellular content of peptide in response to gonadotropins, modulators of gonadotropin action, and inhibitors of protein translation and transcription. The testes of aging rats will also be inspected for the development of any lesions affecting this system. Details of the mechanism by which cAMP promotes a rise in the level of activator peptide will be investigated, with particular effort focused on a model invoking proteolytic generation of the functional peptide from an inactive precursor. A reticulocyte cell-free translation system and pulse-chase experiments will be employed. Additional studies are designed to address the metabolic fate of the peptide. The results of these investigations should markedly enhance our understanding of the way in which gonadotropins regulate a key reaction common to the steroidogenic pathways of their target organs, and may well have relevance for current efforts to control reproductive function in man.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Modified Research Career Development Award (K04)
Project #
5K04HD000613-05
Application #
3073181
Study Section
Biochemical Endocrinology Study Section (BCE)
Project Start
1984-08-01
Project End
1989-07-31
Budget Start
1988-08-01
Budget End
1989-07-31
Support Year
5
Fiscal Year
1988
Total Cost
Indirect Cost
Name
State University of New York at Buffalo
Department
Type
School of Medicine & Dentistry
DUNS #
038633251
City
Buffalo
State
NY
Country
United States
Zip Code
14260
Gregoire, J; Mertz, L M; Pedersen, R C (1993) Glucose-regulated protein-78 expression in the rat adrenal cortex. J Mol Endocrinol 10:33-42
Morphy, M A; Fava, G A; Pedersen, R C et al. (1992) Beta-endorphin responses to metyrapone and dexamethasone in depressed patients. Eur Neuropsychopharmacol 2:421-4
Morphy, M A; Fava, G A; Pedersen, R C et al. (1990) Effects of metyrapone and dexamethasone upon pro-gamma-MSH plasma levels in depressed patients and healthy controls. J Affect Disord 19:183-9
Sonino, N; Fava, G A; Morphy, M A et al. (1990) Effects of metyrapone and dexamethasone on pro-gamma-MSH and ACTH levels in depressed patients. Eur Neuropsychopharmacol 1:63-5
Mertz, L M; Pedersen, R C (1989) The kinetics of steroidogenesis activator polypeptide in the rat adrenal cortex. Effects of adrenocorticotropin, cyclic adenosine 3':5'-monophosphate, cycloheximide, and circadian rhythm. J Biol Chem 264:15274-9
Mertz, L M; Pedersen, R C (1989) Steroidogenesis activator polypeptide may be a product of glucose regulated protein 78 (GRP78). Endocr Res 15:101-15
Frustaci, J; Mertz, L M; Pedersen, R C (1989) Steroidogenesis activator polypeptide (SAP) in the guinea pig adrenal cortex. Mol Cell Endocrinol 64:137-43
Pedersen, R C (1987) Steroidogenesis activator polypeptide (SAP) in the rat ovary and testis. J Steroid Biochem 27:731-5
Pedersen, R C; Brownie, A C (1987) Steroidogenesis-activator polypeptide isolated from a rat Leydig cell tumor. Science 236:188-90
Pedersen, R C; Brownie, A C (1987) Gamma 3-melanotropin promotes mitochondrial cholesterol accumulation in the rat adrenal cortex. Mol Cell Endocrinol 50:149-56

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