Aging and Prostatic Hyperplasia in Transgenic Mice

转基因小鼠的衰老和前列腺增生

• 批准号: 6471945
• 负责人: ARUN K. ROY
• 金额: $ 25.37万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6471945
• 关键词: aging; androgen receptor; benign prostate hyperplasia; disease /disorder model; gene expression; genetic promoter element; genetically modified animals; immunocytochemistry; in situ hybridization; insulinlike growth factor; laboratory mouse; male; microarray technology; model design /development; prostate preneoplastic state; receptor expression

DESCRIPTION (provided by applicant): Age-associated benign prostatic hyperplasia (BPH) is a major health problem of elderly men. The molecular etiology of BPH is complex and not clearly understood. Chronic influence of multiple regulatory factors including androgen and peptide growth factors are suspected to contribute to pro static cell proliferation and pathogenesis. The species-specific nature of BPH and the lack of an appropriate mouse model have impeded progress in the delineation of the causal factors for the development of BPH and testing of potential intervention strategies. It is our hypothesis that prostate-specific overexpression of the androgen receptor (AR) and insulinlike growth factor-1 (IGF- 1) in transgenic mice would cause increased prostatic cell proliferation and would give rise to a pathological condition similar to human BPH. The first specific aim of this proposal is to generate transgenic mice overexpressing AR in the prostate targeted by a ten kilobase pair long homologous mouse probasin gene promoter and to characterize the age-and androgen-dependent changes in the prostatic morphology, cellular composition and gene expression profiles. Region (proximal, intermediate and distal)- and lobe-specific histopathologic changes during aging will be correlated with gene expression profiles determined by micro array analysis. In the second specific aim, we will elucidate the interacting role of AR and IGF-1 in promoting aberrant cell proliferation and gene expression through comparative analysis of monotransgenic mice with individual prostatic overexpression of AR and IGF- 1 and bitransgenic mice with simultaneous overexpression of both AR and IGF- 1 in the prostate. Our preliminary results support the feasibility of the proposed experiments and successful completion of this study is expected to provide important new insights into the cellular and molecular pathways that lead to the development of the prostatic hyperplasia under the influence of physiological stimuli. Additionally, the transgemc model and molecular markers generated through these investigations will be beneficial for future studies concerning the development of effective intervention strategies and progression/remission of the disease process.

描述（由申请人提供）：前列腺相关良性前列腺 前列腺增生（BPH）是老年男性的主要健康问题。分子 BPH的病因是复杂的并且不清楚。慢性影响 包括雄激素和肽生长因子在内的多种调节因子， 被怀疑有助于前列腺细胞增殖和发病。的 前列腺增生的物种特异性和缺乏适当的小鼠模型， 阻碍了在划定发展的因果因素方面取得进展 的BPH和潜在的干预策略的测试。我们假设 前列腺特异性雄激素受体（AR）过度表达， 胰岛素样生长因子-1（IGF- 1）在转基因小鼠中会引起 前列腺细胞增殖，并会引起病理状态 与人类前列腺增生相似。该提案的第一个具体目标是产生 前列腺中过表达AR的转基因小鼠被一种ten β-淀粉酶靶向 配对长同源小鼠probasin基因启动子，并表征年龄和 前列腺形态学、细胞内雄激素依赖性变化 组成和基因表达谱。区域（近端、中间和 远端）和叶特异性组织病理学变化， 与通过微阵列分析确定的基因表达谱相关。在 第二个具体目标，我们将阐明AR和IGF-1的相互作用 在促进异常细胞增殖和基因表达中， 前列腺单转基因小鼠的比较分析 AR和IGF- 1过表达和双转基因小鼠同时 前列腺中AR和IGF- 1的过度表达。我们的初步结果 支持拟议实验的可行性和成功完成 这项研究有望为细胞生物学提供重要的新见解。 以及导致前列腺发育的分子途径 在生理刺激的影响下增生。另夕h transgemc模型和通过这些研究产生的分子标记 将有利于今后的研究，有关发展有效的 干预策略和疾病进程的进展/缓解。