Effects of Aging on Prostate Structure and Function

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（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，即腹侧、背侧和外侧。每个叶在生物化学上是不同的，对雄激素的反应也是不同的。基于胚胎起源和生化功能，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，自发的和雄激素刺激的前列腺上皮细胞增生发生在衰老的褐挪威大鼠的背侧和外侧，而不是腹侧。因此，年龄依赖性、脑叶特异性的褐挪威大鼠前列腺增生被认为是人类前列腺增生的模型。我们的工作假设是，衰老导致前列腺内氧化应激的逐渐增加，其结果是前列腺对雄激素特异性敏感性的改变和细胞调节机制的改变。这些变化很明显

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.