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）：本项目中提出的工作的长期目标是提供生物信息的坚实基础，从而了解人体前列腺体内正常和病理生长过程。 本申请的中心假设是前列腺的上皮和基质区室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（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节。TGF β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TGF β配体，受体和TGF β信号通路在人前列腺组织中的下游激活的表达和作用。 然后，我们将研究选择性地删除表达或可控地过表达这些蛋白质在体内人前列腺组织中的影响，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的机制作用，TGF β信号在维持成人稳态调节上皮细胞和基质细胞之间的旁分泌相互作用，以及如何在这种信号的不适当的变化可能模仿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人前列腺组织中的表达和性类固醇激素调节。 具体目标二：体内生长、生长-静止和退化的人前列腺组织中TGF β信号传导受控过表达对下游信号传导途径的影响。 具体目标3：生长、生长-静止和生长期TGF β信号转导的受控缺失 在体内使人前列腺组织退化，机械作用。