Elucidation of molecular and cellular mechanisms of androgen action has been the long-term objective of this research project. Effects of androgens on growth and function of target organs are currently though to be mediated by both a direct action of the hormone and indirectly by androgen-stimulated synthesis and secretions of paracrine growth factors. An imbalance of these direct and indirect effects can potentially cause abnormal growth and function of target organs such as the prostate gland. The keratinocyte growth factor (KGF), a member of the fibroblast growth factor family, is produced by the prostatic stromal cells and serves as a paracrine mediator of androgen action on the prostatic epithelium. This renewal application is designed to induce prostates hyperplasia in transgenic mice, by creating an imbalance between the direct and indirectly acting hormonal mediators, in order to study the specific contributory roles of KGF and androgens on prostatic function and to examine intervention strategies to retard the hyperplastic growth of the gland. Specific research objectives include (i) Overexpression of the androgen receptor (AR) and KGF, targeted to prostatic epithelial cells by the probasin gene promoter. This objective is based on the hypothesis that the age-dependent development of porstaic hyperplasia in the human may initially be due to increase epithelial growth which subsequently leads to the formation of cysts and nodules with thickening of the surrounding stroma. (ii) Stimulation of abnormal prostatic wroth in mice overexpressing AR directed by KGF gene promoter. The hypothesis behind this objective is based on our previous finding of an age-invariant overexpression of AR in prostic stromal cells of the dog, an animal that shows continued enlargement of the prostate with aging. (iii) the third and the final specific aim of this application is to generate transgenic mice engineered to express an AR mRNA inactivating ribozyme in the prostatic epithelium constitutively, and under conditional induction mediated by RU486. The RU486- dependent binary switch model will allow a transient inactivation of AR in the epithelium without interference with the stromal function. Based on the initial data, a successful outcome of all of these research objectives is anticipated. Completion of these investigative tools for studying hyperplastic growth of the prostate gland.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK014744-29
Application #
2770338
Study Section
Endocrinology Study Section (END)
Program Officer
Margolis, Ronald N
Project Start
1988-02-01
Project End
2001-08-31
Budget Start
1998-09-18
Budget End
1999-08-31
Support Year
29
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Texas Health Science Center San Antonio
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229
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Roy, Arun K; Oh, Thomas; Rivera, Omar et al. (2002) Impacts of transcriptional regulation on aging and senescence. Ageing Res Rev 1:367-80
Roy, A K; Tyagi, R K; Song, C S et al. (2001) Androgen receptor: structural domains and functional dynamics after ligand-receptor interaction. Ann N Y Acad Sci 949:44-57
Tyagi, R K; Lavrovsky, Y; Ahn, S C et al. (2000) Dynamics of intracellular movement and nucleocytoplasmic recycling of the ligand-activated androgen receptor in living cells. Mol Endocrinol 14:1162-74
Lavrovsky, Y; Chatterjee, B; Clark, R A et al. (2000) Role of redox-regulated transcription factors in inflammation, aging and age-related diseases. Exp Gerontol 35:521-32
Song, C S; Jung, M H; Supakar, P C et al. (1999) Negative regulation of the androgen receptor gene promoter by NFI and an adjacently located multiprotein-binding site. Mol Endocrinol 13:1487-96
Lavrovsky, Y; Tyagi, R K; Chen, S et al. (1999) Ribozyme-mediated cleavage of the estrogen receptor messenger RNA and inhibition of receptor function in target cells. Mol Endocrinol 13:925-34
Lavrovsky, Y; Song, C S; Chatterjee, B et al. (1998) A rapid and reliable PCR-based assay for gene transmission and sex determination in newborn transgenic mice. Transgenic Res 7:319-20
Chen, S; Song, C S; Lavrovsky, Y et al. (1998) Catalytic cleavage of the androgen receptor messenger RNA and functional inhibition of androgen receptor activity by a hammerhead ribozyme. Mol Endocrinol 12:1558-66
Rikke, B A; Vellanoweth, R L; Her, S et al. (1995) Cloning and sequence analysis of a novel member of the single-stranded DNA binding protein family. Biochim Biophys Acta 1261:143-6

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