Aging and Prostatic Hyperplasia in Transgenic Mice

转基因小鼠的衰老和前列腺增生

• 批准号: 6631430
• 负责人: BANDANA CHATTERJEE
• 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/6631430
• 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(申请人提供)：与年龄相关的良性前列腺 前列腺增生症(BPH)是老年男性的主要健康问题。分子 良性前列腺增生症的病因很复杂，目前尚不清楚。的慢性影响 包括雄激素和肽生长因子在内的多种调节因子 怀疑有助于促进细胞增殖和致病。这个 BPH的物种特异性和缺乏合适的小鼠模型 妨碍在界定发展的因果因素方面取得进展 对良性前列腺增生症和潜在干预策略的测试。这是我们的假设 前列腺特异性雄激素受体(AR)和 胰岛素样生长因子-1(IGF-1)在转基因小鼠体内的表达 前列腺细胞增殖，并会引起病理情况 类似于人类的良性前列腺增生症。这项提议的第一个具体目标是产生 以10kb碱基为靶点的前列腺过度表达AR转基因小鼠 双长同源小鼠前盆基因启动子并鉴定AGE-和 雄激素依赖性前列腺细胞形态的改变 成分和基因表达谱。区域(近端、中间端和 远端)--和叶在衰老过程中的特殊组织病理学变化 与微阵列分析确定的基因表达谱相关。在……里面 第二个具体目的，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方面 前列腺单基因转基因小鼠的比较分析 AR和IGF-1的过度表达与双转基因小鼠 前列腺癌组织中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并成功完成 这项研究的成果有望为我们提供对细胞 以及导致前列腺发育的分子途径 生理刺激影响下的增生症。此外， 易位模型和通过这些研究产生的分子标记 这将有利于今后关于有效开发的研究 干预策略和疾病进程的进展/缓解。