Effects of Aging on Prostate Structure and Function

衰老对前列腺结构和功能的影响

• 批准号: 7026509
• 负责人: TERRY R. BROWN
• 金额: $ 35.92万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7026509
• 关键词: DNA damage; aging; androgens; benign prostate hyperplasia; biological signal transduction; cell growth regulation; cell proliferation; cyclin dependent kinase; dietary restriction; epidermal growth factor; estradiol; fibroblast growth factor; growth factor receptors; hormone regulation /control mechanism; hormone sensitivity /resistance; insulinlike growth factor; laboratory rat; nutrition related tag; oncoprotein p21; organ culture; oxidative stress; prostate; receptor expression; testosterone; transforming growth factors

DESCRIPTION (provided by applicant): Aging is a major factor that contributes to abnormal growth of the prostate leading to the condition of benign prostatic hyperplasia (BPH) in men. Unlike the human prostate, the rodent prostate is organized into different anatomical lobes referred to as the ventral, dorsal and lateral. Each lobe is biochemically distinct and differentially responsive to androgens. Based upon embryologic origin and biochemical function, the lateral and dorsal lobes have been considered homologous to the human prostate, whereas the ventral lobe lacks homology. Past studies in our laboratory have established that spontaneous and androgen-stimulated prostate epithelial cell hyperplasia occurs in the dorsal and lateral, but not the ventral lobe of aging Brown Norway rats. Hence, the age-dependent, lobe-specific prostatic hyperplasia of Brown Norway rats is considered to be a model for human BPH. Our working hypothesis is that aging contributes to a progressive increase in oxidative stress within the prostate, the consequences of which are alterations in the lobe-specific sensitivity to androgen and alterations in cell regulatory mechanisms. These alterations manifest themselves in the form or reactivated cell proliferation and increased cell survival, with the net effect being cellular hyperplasia. The lobe-specific, age-dependent occurrence of hyperplasia provides a unique model to understand the factors that differentially contribute to hyperplasia. In this application, we propose three aims to determine: 1) if changes in androgen sensitivity alter the expression of cell cycle regulatory molecules that activate cell proliferation leading to hyperplasia; 2) if changes in growth factor regulation and expression increase cell proliferation and survival leading to hyperplasia; and 3) if oxidative stress causes damage to lipids, proteins and DNA that correlates with disruption of normal regulation of prostate growth. These studies should lead to a better understanding of the molecular mechanisms that underlie the incidence of prostatic hyperplasia with increasing age, particularly at a time in life when the androgendependent prostate is exposed to a hormonal milieu with paradoxically diminished testosterone concentration.

描述（由申请人提供）：衰老是导致前列腺异常生长的主要因素，导致男性良性前列腺增生（BPH）的状况。与人类前列腺不同，啮齿动物前列腺被组织成不同的解剖叶，称为腹侧，背和侧面。每个叶在生化上是不同的，并且对雄激素有差异响应。基于胚胎的起源和生化功能，外侧和背叶被认为与人前列腺同源，而腹叶缺乏同源性。我们实验室的过去研究表明，在背侧和外侧发生了自发和雄激素刺激的前列腺上皮细胞增生，但不发生衰老的棕色挪威大鼠的腹叶。因此，棕色挪威大鼠的年龄依赖性，叶特异性的前列腺增生被认为是人类BPH的模型。我们的工作假设是，衰老有助于前列腺内氧化应激的逐渐增加，其后果是叶对雄激素的敏感性的改变以及细胞调节机制的改变。这些改变体现了 其本身的形式或重新激活的细胞增殖并增加了细胞存活，其净作用是细胞增生。增生的叶特异性，年龄依赖性的发生提供了一个独特的模型，以了解有助于增生的因素。在此应用中，我们提出三个目的是确定：1​​）如果雄激素敏感性的变化改变了激活细胞增殖导致增生的细胞周期调节分子的表达； 2）如果生长因子调节和表达的变化会增加细胞增殖和存活，从而导致增生； 3）如果氧化应激会损害脂质，蛋白质和DNA与正常调节前列腺生长有关。这些研究应使人们更好地理解前列腺增生率随着年龄的增长的发生率的分子机制，尤其是在生命中依赖雄激素前列腺的生命时期暴露于激素环境中，睾丸激素浓度降低了。