The focus of this proposal is to define the roles of neurotransmitters alone or in combination with androgen in regulation of the growth and differentiation of the rat ventral prostate gland (VP). This new concept of the involvement of neurotransmitters in androgen action in the rat VP was conceived following our recent observation that the activation of beta- adrenergic receptors by the norepinephrine or isoproterenol is closely associated with androgen-induced activation of DNA synthesis and the accumulation of a differentiative and androgen- dependent rat VP epithelial protein, the prostatic binding protein (PBP), in tissues. The following objectives will be pursued: 1. Both systemic (subcutaneous injections) and local (sustained release Elvax implant) effect of dihydrotestosterone and alpha- or beta-adrenergic agonist on co-regulating the growth (DNA content) and differentiation (PBP content) of the rat VP will be investigated. The possible local irreversible effects induced by chemical sympathectomy on androgen-induced growth and differentiative responses of the rat VP will be compared to the prostate gland in intact hosts. 2. The direct of adrenergic agonists or antagonists and the combined effects of these adrenergic drugs with androgen on DNA and PBP synthesis in cultured prostatic epithelial and co-cultured epithelial and stromal cells will be investigated. 3. The mechanism(s) of action of co-regulation by neurotransmitters and androgenic steroids on rat VP will be investigated. a. We will characterize the adrenergic and serotonergic receptors in rat VP under various hormonal and growth conditions. b. We will determine the interrelationship between beta- adrenergic receptor-mediated adenylate cyclase pathway and the nuclear androgen receptor pathway on the overall growth and differentiative functions of the rat VP. The use of specific antagonists for each of the pathways will be emphasized. c. We will assess PBP expression by rat VP both at the level of transcription and translation under the influence of either adrenergic agonists or androgenic steroids or both. The study will further advance our understanding of the possible combined action of neural and endocrine factors on the maintenance of normal functions of the prostate gland and provide a rationale for future development of new therapeutic approaches for the management of neoplastic prostatic disease in man.
| Guthrie, P D; Freeman, M R; Liao, S T et al. (1990) Regulation of gene expression in rat prostate by androgen and beta-adrenergic receptor pathways. Mol Endocrinol 4:1343-53 |
