PROSTATIC STEROIDS AND SECOND MESSENGERS

前列腺类固醇和第二信使

• 批准号: 6163785
• 负责人: William Rosner
• 金额: $ 23.59万
• 依托单位: ST. LUKE'S-ROOSEVELT INST FOR HLTH SCIS
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-03-11 至 2002-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6163785
• 关键词: androgens; benign prostate hyperplasia; cell membrane; clinical research; cyclic AMP; gel mobility shift assay; gene expression; genetic transcription; globulins; growth factor; hormone binding protein; human subject; male; northern blottings; prostate; prostate specific antigen; receptor binding; second messengers; secretion; site directed mutagenesis; steroid hormone metabolism; steroid hormone receptor; tissue /cell culture; western blottings

At autopsy, 50 percent of men aged 51-60 have histologic criteria for benign prostatic hyperplasia (BPH), and this incidence increases with age. This high incidence of BPH translates into about 300,000 surgical procedures per year at a cost of over one billion dollars annually. In spite of the high cost in disability and dollars, our initimate, detailed knowledge of the causes of BPH remains inadequate. Studies of androgens, the most intensively examined group of substances in the control of prostatic growth, and estrogens have failed to explain the definitive events leading to BPH. It long has been known that the presence of testis and aging are necessary for BPH to occur. However, it is most puzzling that as the frequency of BPH goes up with age, the most important acknowledged physiologic stiumlus to prostatic growth, testosterone, falls in plasma and the concentration of its binding protein, sex hormone- binding globulin (SHBG), rises. Further, within the prostate, testosterone does not rise with age in either stroma or epithelium, while dihydrotestosteron (DHT) is constant with age in stroma and falls substantially in epithelium. Recent observations may explain these inconsistencies and open new areas of understanding and therapy. Androgens and estrogens exert their effects through intracellular receptors. Attempts to unravel the role of androgens and estrogens in BPH rely on this well-established model as a basis from which to go forward. It has been demonstrated that the prostate contains an additional signaling system for androgens and estrogens that functions through the intermediacy of a receptor (RSHBG) for plasma SHBG. Using this signalling pathway, these steroids engender rapid rises in intracellular cAMP. We have shown that the system is involved in both growth and the nonligand activation of the androgen receptor. Others have shown that cAMP is a powerful modulator of the transciptional effects of endogen and estrogen receptors; however, virtually nothing is known of how cAMP-induced modulation or transcription is physiologically regulated. The RSHBG system is an ideal candidate to be such a regulator. Our long term objective is to integrate this new steroid signaling system into the general mechanisms of steroid hormone action in the prostate. Our specific aims in this applicatin include: unraveling the mechanism of RSHBG-induced activation of PSA secretion in the absence of androgens, examination of the mechanisms of RSHBG modulation of estrogen and androgen- induced gene transcription, and determination of the relationships among RSHBG, cAMP response element-dependent gene transcription and prostate growth.

在尸检时，51-60岁的男性中有50％具有组织学标准 对于良性前列腺增生（BPH），此发生率 随着年龄的增长而增加。 BPH的高发病率转化为 每年约30万手术程序，费用超过一个 每年十亿美元。 尽管残疾成本很高， 美元，我们对BPH原因的初始，详细的知识 仍然不足。 对雄激素的研究，最深入的研究组 控制前列腺生长和雌激素的物质具有 未能解释导致BPH的确定事件。 长期有 众所周知，睾丸和衰老的存在是必要的 BPH发生。 但是，最令人困惑的是，随着频率 BPH随着年龄的增长而上升，是最重要的公认 生理lus前列腺生长，睾丸激素，属于 血浆及其结合蛋白的浓度，性激素 - 结合球蛋白（SHBG），上升。 此外，在前列腺内， 睾丸激素在基质或上皮的年龄均不增长， 二氢睾丸激素（DHT）随着基质的年龄而恒定，并且 大幅落在上皮。 最近的观察可能解释这些不一致并开放 新的理解和治疗领域。 雄激素和 雌激素通过细胞内受体发挥作用。 试图揭示雄激素和雌激素在BPH中的作用 依靠这个良好的模型作为可以从中获得的基础 向前。 已经证明前列腺包含 雄激素和雌激素的其他信号系统 通过受体（RSHBG）的中介功能的功能 血浆SHBG。 使用这些信号通路，这些类固醇 在细胞内营地中快速上升。 我们已经表明 该系统参与生长和非配体激活 雄激素受体。 其他人表明营地是一个 内源和 雌激素受体；但是，几乎什么都不知道 营地引起的调节或转录在生理上是 受监管。 RSHBG系统是这样的理想候选人 监管机构。 我们的长期目标是整合这种新的类固醇信号 系统进入类固醇激素作用的一般机制 前列腺。 我们在此应用程序中的具体目标包括： 阐明RSHBG诱导的PSA激活的机制 在没有雄激素的情况下分泌，检查 RSHBG调制雌激素和雄激素的机制 诱导基因转录和关系的确定 在RSHBG中，cAMP响应元件依赖性基因 转录和前列腺生长。