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: 6866404
• 负责人: TERRY R. BROWN
• 金额: $ 36.79万
• 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/6866404
• 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）：年龄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）。与人类前列腺不同，啮齿动物前列腺被组织成不同的解剖学叶，称为腹侧、背侧和侧叶。每个叶在生化上是不同的，对雄激素的反应也不同。基于胚胎学起源和生化功能，侧叶和背叶被认为与人类前列腺同源，而腹叶缺乏同源性。我们实验室过去的研究已经确定，自发性和雄激素刺激的前列腺上皮细胞增生发生在背侧和外侧，但不是老化的布朗挪威大鼠的腹侧叶。因此，Brown Norway大鼠的年龄依赖性、叶特异性前列腺增生被认为是人类BPH的模型。我们的工作假设是，老化有助于前列腺内的氧化应激的逐步增加，其后果是改变叶特异性的雄激素敏感性和细胞调节机制的改变。这些变化表明 它们本身以重新激活细胞增殖和增加细胞存活的形式存在，净效应是细胞增生。叶特异性，年龄依赖性增生的发生提供了一个独特的模型，以了解不同的因素，有助于增生。在本申请中，我们提出了三个目的来确定：1）雄激素敏感性的变化是否改变激活细胞增殖导致增生的细胞周期调节分子的表达; 2）生长因子调节和表达的变化是否增加细胞增殖和存活导致增生;和3）如果氧化应激引起与前列腺生长的正常调节的破坏相关的脂质、蛋白质和DNA的损伤。这些研究应导致更好地理解的分子机制，前列腺增生的发病率随着年龄的增长，特别是在生活中的时间，当雄激素依赖性前列腺暴露于激素环境与矛盾减少睾酮浓度。