EFFECTS OF AGING ON THE ANDROGEN SENSITIVITY OF SEX ACCESSORY TISSUES

衰老对性附属组织雄激素敏感性的影响

• 批准号: 6299278
• 负责人: TERRY R. BROWN
• 金额: $ 19.52万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-15 至 2001-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6299278
• 关键词: Leydig cells; aging; androgen inhibitor; androgen receptor; biomarker; cell age; cell growth regulation; cell type; dihydrotestosterone; endocrine pharmacology; estradiol; hormone regulation /control mechanism; hyperplasia; immunocytochemistry; laboratory rat; male; male castration; northern blottings; prostate; radioimmunoassay; receptor binding; seminal vesicles; testosterone; testosterone 5 alpha reductase; western blottings

Prostatic cell hyperplasia occurs in the dorsal and lateral lobes, but not the ventral lobe, of the aging Brown Norway rat. These findings suggest that androgen sensitivity of the Brown Norway rat prostate is lobe-specific and age-dependent. Therefore, we propose to investigate age-specific changes in the regulation of growth and differentiated cell structure and function in aging Brown Norway rats to elucidate the mechanisms of prostatic hyperplasia. The specific aims of this proposal are: 1) we will measure serum and tissue concentrations of testosterone (T), and its active metabolites dihydrotestosterone (DHT) and estradiol (E2) and determine whether changes in androgen or estrogen receptors, 5alpha- reductase or aromatase activities occur within each lobe; 2) we will determine whether age-associated intrinsic changes occur within each lobe to affect androgen sensitivity. We will pharmacologically alter androgen receptor binding, 5alpha-reductase activity and DHT levels or aromatase activity and E2 levels in young and old rats and determine whether cell specific structure and function is affected; 3) we will determine whether age-dependent and lobe-specific differences occur in cell death and cell proliferation following castration alone or when androgen is replaced; and 4) we will determine whether lobe-specific cellular hyperplasia is related to age-dependent changes in the magnitude or temporal pattern of testicular testosterone production. Growth within the ventral, lateral and dorsal prostate lobes will be assessed by tissue weight; cell structure by microscopic examination of call morphology and stereologic analysis of cell number within epithelial and stromal compartments; and function by Northern blots of specific mRNAs and Western blots of specific proteins for androgen receptor and 5alpha-reductase in all tissues, for prostate in, dorsal protein I and probasin in the ventral, dorsal and lateral prostate lobes, respectively. Growth factors and their receptors will be related to changes in androgen sensitivity and in cellular morphology. Immunocytochemistry and in situ RNA hybridization will be used to localize cell-specific expression of gene products.

前列腺细胞增生发生在背叶和侧叶，但 而不是年迈的棕色挪威鼠的腹叶。这些 研究结果表明，棕色挪威大鼠对雄激素的敏感性 前列腺叶是特定的，与年龄有关。因此，我们建议 研究生长和发育调节的特定年龄变化 衰老的棕色挪威人分化的细胞结构和功能 以阐明大鼠前列腺增生症的发病机制。这个 这项建议的具体目标是：1)我们将检测血清和 组织中睾酮(T)及其活性代谢产物的浓度 双氢睾酮(DHT)和雌二醇(E_2)并测定 无论是雄激素还是雌激素受体的变化，5α- 还原酶或芳香酶活性发生在每个叶中；2)我们将 确定与年龄相关的内在变化是否在 每一叶都会影响雄激素敏感性。我们会 药理改变雄激素受体结合，5α-还原酶 活性和DHT水平或芳香酶活性和E_2水平 并确定细胞的特定结构和 功能受到影响；3)我们将确定是否依赖于年龄 叶特异性差异出现在细胞死亡和细胞 单独去势后或雄激素治疗后的增殖 替换；以及4)我们将确定叶特定的细胞 增生性疾病与年龄相关的大小或 睾丸睾酮产生的时间模式。生长 在腹侧、外侧和背侧的前列腺小叶内将被评估 通过组织重量；通过显微镜检查CALL的细胞结构 上皮内细胞数量的形态和体视学分析 和间质隔室；并通过Northern印迹 雄激素特异性蛋白的特异性mRNAs和Western blotts 受体和5α-还原酶在所有组织中的表达，对于背部的前列腺 蛋白I与前列腺腹侧、背侧和外侧的前盆 分别为叶。生长因子及其受体将是 与雄激素敏感性的变化和细胞内 形态学。免疫细胞化学和原位RNA杂交 将被用来定位基因产物的细胞特异性表达。