Paracrine Regulation of Benign Prostate Hyperplasia Pathogenesis

描述(由申请人提供)：本项目建议的工作的长期目标是提供坚实的生物学信息基础，使人们能够了解活体内人类前列腺正常和病理生长所涉及的过程。这一应用的中心假设是前列腺上皮和间质之间的旁分泌相互作用是BPH发病的原因。转化生长因子-β(TGFβ)及其受体(TGFβ-R)参与调节前列腺上皮细胞的增殖和凋亡。转化生长因子β也被认为与前列腺间质中的一种平滑肌表型的分化有关。我们将研究转化生长因子β配体、受体在人前列腺组织中的表达和作用以及转化生长因子β信号通路的下游激活。然后，我们将在活体内检测这些蛋白在人前列腺组织中选择性表达或可控过度表达的效果，以确定它们对上皮和间质分化的影响，从而确定它们调节前列腺病理的能力。这项工作的重点是证明TGFbeta信号通过调节上皮细胞和基质细胞之间的旁分泌相互作用在维持成体动态平衡中所起的机制作用，以及这种信号的不适当变化如何模拟BPH。具体目标如下：特定目标1：TGFβ信号分子在发育中、正常成人和增生性成人前列腺组织中的表达及性激素调节。特定目标2：体内生长、生长停滞和退化的人前列腺组织中TGFbeta信号受控过表达对下游信号通路的影响。具体目标3：在生长、生长停滞和 体内人体前列腺组织退行性变，机械效应。

DESCRIPTION (provided by applicant): 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.