The goal of the proposed research is to determine whether age- related reductions in sperm production in male mammals are due to intrinsic aging processes ongoing in the spermatogenic cells themselves, or rather represents the manifestation of extrinsic defects that accumulate in the supporting somatic elements. A correlary to this question is whether the germ cells, which must by definition, retain their totipotency in order to give rise to succeeding generations,are subject to the normal aging processes that affect somatic cell types. Because spermatogenesis is heavily dependent on somatic cell functions, including endocrine functions mediated by the hypothalamus-pituitary-Leydig cell axis, as well as direct interactions with supporting Sertoli cells, it may well be that age-related diminution of reproductive capacity in the male is completely the result of accumulating defects in supporting somatic functions. If this is true, it would have major significance for the potential treatment of age-related reproductive incapacity in human males. This application proposes to address these questions by analyzing specific gene expression in the germ cells as a function of age and/perturbation of supporting somatic cell functions as follows:
Specific Aim #1 - Isolate clones of genes transcribed in male embryonic germ cells but not in male embryonic somatic cells, and analyze the subsequent expression to these sequences in male germ cells at later stages in the fetus and adult.
Specific Aim #2 - Measure levels of specific mRNAs in spermatogenic cells from young, middle-aged and old animals, to see if there are any apparent age- related changes in the transcription of specific genes in these cells. Also test for an age-related reappearance of mRNAs from genes normally transcribed only in earlier stages in the germ line.
Specific Aim #3 - Compare the effects on gene expression in adult spermatogenic cells in young versus old animals of treating with: 1) EDS to eliminate testos-terone-producing Leydig cells; 2) testosterone-estrogen implants to specifically reduce testosterone levels; and 3) gamma irradiation to destroy specific spermatogenic cells.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG008321-02
Application #
3809435
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Type
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Jervis, Kathryn M; Robaire, Bernard (2004) The effects of long-term vitamin E treatment on gene expression and oxidative stress damage in the aging Brown Norway rat epididymis. Biol Reprod 71:1088-95
Zubkova, Ekaterina V; Robaire, Bernard (2004) Effect of glutathione depletion on antioxidant enzymes in the epididymis, seminal vesicles, and liver and on spermatozoa motility in the aging brown Norway rat. Biol Reprod 71:1002-8
Anway, Matthew D; Folmer, Janet; Wright, William W et al. (2003) Isolation of sertoli cells from adult rat testes: an approach to ex vivo studies of Sertoli cell function. Biol Reprod 68:996-1002
Ezer, Nadine; Robaire, Bernard (2003) Gene expression is differentially regulated in the epididymis after orchidectomy. Endocrinology 144:975-88
Jervis, Kathryn M; Robaire, Bernard (2002) Changes in gene expression during aging in the Brown Norway rat epididymis. Exp Gerontol 37:897-906
Banerjee, Partha P; Banerjee, Subhadra; Brown, Terry R (2002) Bcl-2 protein expression correlates with cell survival and androgen independence in rat prostatic lobes. Endocrinology 143:1825-32
Chen, Haolin; Hardy, Matthew P; Zirkin, Barry R (2002) Age-related decreases in Leydig cell testosterone production are not restored by exposure to LH in vitro. Endocrinology 143:1637-42
Culty, Martine; Luo, Lindi; Yao, Zhi-Xing et al. (2002) Cholesterol transport, peripheral benzodiazepine receptor, and steroidogenesis in aging Leydig cells. J Androl 23:439-47
Luo, L; Chen, H; Zirkin, B R (2001) Leydig cell aging: steroidogenic acute regulatory protein (StAR) and cholesterol side-chain cleavage enzyme. J Androl 22:149-56
Jervis, K M; Robaire, B (2001) Dynamic changes in gene expression along the rat epididymis. Biol Reprod 65:696-703

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