The long-term objective of the work proposed in this project is to provide a firm groundwork of biological information allowing an understanding of the processes involved in the normal and pathological growth of the human prostate in vivo. The central hypothesis of this application is that paracrine interactions between the epithelial and stromal compartments of the prostate are responsible for BPH pathogenesis. The transforming growth factor-betas (TGFbeta) and their receptors (TGFbeta-R) are implicated in the regulation of proliferation and apoptosis in the prostatic epithelium. TGFbeta is also thought to be involved in the differentiation of a smooth muscle phenotype in the prostatic stroma. We will examine the expression and role of TGFbeta ligands, receptors and downstream activation of the TGFbeta signaling pathway in human prostatic tissue. We will then examine the effects of selectively either deleting expression or controllably over expressing these proteins in human prostatic tissue in vivo to determine their effects on epithelial and stromal differentiation and thus determine their ability to regulate prostatic pathology. The focus of this work is to demonstrate the mechanistic role, which TGFbeta signaling plays in maintaining adult homeostasis by regulating paracrine interactions between epithelial and stromal cells, and how inappropriate changes in such signaling might mimic BPH. The following specific aims will be pursued:
Specific Aim 1 : Expression and sex steroid hormone regulation of TGFbeta signaling molecules in developing, normal adult and hyperplastic adult human prostatic tissue.
Specific Aim 2 : Effects on downstream signaling pathways of controlled overexpression of TGFbeta signaling in growing, growth-quiescent, and regressing human prostatic tissue in vivo.
Specific Aim 3 : Controlled deletion of TGFbeta signaling in growing, growth-quiescent, and regressing human prostatic tissue in vivo, mechanistic effects.
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