Paracrine Regulation of BPH Pathogenesis

描述（由申请人提供）：本项目提出的工作的长期目标是为生物信息提供坚实的基础，从而了解体内人类前列腺正常和病理生长的过程。本应用的中心假设是前列腺上皮和间质室之间的旁分泌相互作用是BPH发病的原因。转化生长因子- β (tgf β)及其受体（tgf β - r）参与前列腺上皮细胞增殖和凋亡的调控。tgf β也被认为参与了前列腺基质中平滑肌表型的分化。我们将研究tgf β配体、受体的表达和作用，以及tgf β信号通路的下游激活。然后，我们将在人体前列腺组织中检查选择性地删除表达或控制过表达这些蛋白的影响，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tgfβ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来维持成人体内平衡的机制作用，以及这种信号的不适当变化如何模拟BPH。具体目标1:tgf β信号分子在发育中、正常成人和增生成人前列腺组织中的表达和性类固醇激素调节。特异性目的2：体内生长、生长静止和退化的人前列腺组织中tgf - β信号的控制过表达对下游信号通路的影响。特异性目标3：生长、生长静止和

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.