SYSTEMS MODELING OF PROSTATE REGULATION AND RESPONSE TO ANTIANDROGEN
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A biologically-based, systems-level model will be developed describing the regulation of the prostate by androgens. The model will extend an existing model for the male rat central axis, which describes feedback between luteinizing hormone and testosterone production in the testes, to include the prostate and conversion of testosterone to dihydrotestosterone (DHT). The prostate model will describe binding of androgens to the androgen receptor, 5α-reductase catalyzed production of DHT, and gene regulation affecting cell proliferation, apoptosis, and prostatic fluid production. The model will combine pharmacokinetic models for endogenous hormones (i.e., testosterone, DHT, LH) and exogenous antiandrogens (e.g., finasteride, flutamide or casodex, vinclozolin), and a pharmacodynamic model for androgen-dependent prostate functions. Linkages of this model with genomics data obtained with castration, testosterone treatments, or antiandrogen treatment will be explored to assist in developing perspectives on how such data would fit into quantitative risk assessments.
Background
Abstract
The prostate is an androgen-dependent tissue that is an important site of disease in human males as well as an important indicator of androgen status in animals. The rat prostate is used for studying antiandrogenic drugs as well as for evaluation of endocrine disruption (e.g., Hershberger Assay). Pubertal changes in the prostate have been observed to be as sensitive to environmental antiandrogens as in utero effects. The goal of this research is to model the biology of prostate androgen function on a systems level to determine the factors responsible for the dose-response observable with androgens and antiandrogens in the male rat. This includes investigation of the roles of positive and negative feedback loops in prostatic response following castration and dosing with testosterone and/or antiandrogens.History/Chronology
| Date | Description |
|---|---|
| 01- FY06 | Report on the prostate function model following castration. |
| 02- FY07 | Report on dose-response with testosterone and/or antiandrogens. |
| 03- FY08 | Evaluate linkage of the biologically-based model of prostate androgen-dependent gene regulation with genomics data. |
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