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: 6615886
• 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/6615886
• 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)：衰老是导致男性前列腺异常生长导致良性前列腺增生症(BPH)的主要因素。与人类的前列腺不同，啮齿动物的前列腺被组织成不同的解剖叶，称为腹叶、背叶和侧叶。每个叶在生物化学上是不同的，对雄激素有不同的反应。根据胚胎起源和生化功能，外侧叶和背叶被认为与人类前列腺同源，而腹叶则缺乏同源性。我们实验室过去的研究已经证实，自发性和雄激素刺激的前列腺上皮细胞增殖发生在老年Brown挪威大鼠的背侧和外侧，而不是腹叶。因此，棕色挪威大鼠的年龄依赖性、叶特异性前列腺增生症被认为是人类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进行性增加，其后果是叶特异性雄激素敏感性的改变和细胞调节机制的改变。这些变化很明显 它们自身的形式或重新激活细胞增殖和增加细胞存活率，其净影响是细胞增殖。肺叶特定的、与年龄相关的增生症的发生为理解导致增生症的不同因素提供了一个独特的模型。在这一应用中，我们提出了三个目标来确定：1)雄激素敏感性的变化是否会改变激活细胞增殖的细胞周期调控分子的表达，从而导致增殖；2)生长因子调控和表达的变化是否会增加细胞的增殖和存活，从而导致增生；以及3)氧化应激是否会导致脂质、蛋白质和DNA的损伤，从而破坏正常的前列腺生长调节。这些研究应该有助于更好地理解随着年龄的增长而导致前列腺增生发生率的分子机制，特别是在依赖雄激素的前列腺暴露在激素环境中，睾酮浓度反常下降的情况下。