Paracrine Regulation of Benign Prostate Hyperplasia Pathogenesis

良性前列腺增生发病机制的旁分泌调节

• 批准号: 7221941
• 负责人: Simon W Hayward
• 金额: $ 25.2万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-15 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7221941
• 关键词: Address; Adolescent; Adrenergic Antagonists; Adrenergic alpha-Antagonists; Adult; Aging; Apoptosis; Benign; Benign Prostatic Hypertrophy; Biological; Bladder; Combined Modality Therapy; Condition; Development; Disease regression; Doxazosin; Epithelial; Epithelial-Stromal Communication; Finasteride; Gland; Gonadal Steroid Hormones; Growth; Health Care Costs; Homeostasis; Human; Hyperplasia; Intervention; Ligands; Malignant - descriptor; Medical; Modeling; Morbidity - disease rate; National Institute of Diabetes and Digestive and Kidney Diseases; Numbers; Obstruction; Operative Surgical Procedures; Oxidoreductase; Pathogenesis; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Play; Process; Prostate; Prostatic; Prostatic Epithelium; Prostatic Stroma; Prostatic Tissue; Protein Overexpression; Proteins; Randomized; Regulation; Role; Score; Signal Pathway; Signal Transduction; Signaling Molecule; Smooth Muscle; Stromal Cells; Symptoms; Thinking; Tissue Recombination; Tissues; Transforming Growth Factor beta; Work; Xenograft Model; body system; concept; cost; design; fetal; hormone regulation; in vivo; inhibitor/antagonist; insight; men; new growth; paracrine; receptor

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.

描述（由申请人提供）：该项目提出的工作的长期目标是提供坚实的生物信息基础，以便了解人类前列腺体内正常和病理生长所涉及的过程。 本申请的中心假设是前列腺上皮区和基质区之间的旁分泌相互作用是 BPH 发病机制的原因。 转化生长因子-β (TGFbeta) 及其受体 (TGFbeta-R) 参与前列腺上皮增殖和凋亡的调节。 TGFbeta 也被认为参与前列腺基质中平滑肌表型的分化。 我们将研究人类前列腺组织中 TGFbeta 配体、受体的表达和作用以及 TGFbeta 信号通路的下游激活。 然后，我们将检查在体内人前列腺组织中选择性删除表达或可控过度表达这些蛋白质的效果，以确定它们对上皮和基质分化的影响，从而确定它们调节前列腺病理学的能力。 这项工作的重点是证明 TGFbeta 信号传导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，以及此类信号传导的不适当变化如何模仿 BPH。 将追求以下具体目标： 具体目标1：TGFbeta信号分子在发育中的正常成人和增生性成人前列腺组织中的表达和性类固醇激素调节。 具体目标 2：体内生长、生长静止和退化的人前列腺组织中 TGFbeta 信号传导受控过度表达对下游信号传导途径的影响。 具体目标 3：在生长、生长静止和生长过程中控制 TGFbeta 信号传导缺失 体内退化人体前列腺组织的机械效应。