AGING AND ANDROGEN RECEPTOR GENE REGULATION

衰老与雄激素受体基因调控

• 批准号: 2692842
• 负责人: ARUN K. ROY
• 金额: $ 22.8万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-01-01 至 2002-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2692842
• 关键词: DNA binding protein; aging; androgen receptor; animal old age; developmental genetics; enhancer binding protein; genetic regulation; genetic regulatory element; high performance liquid chromatography; laboratory rat; liver; molecular cloning; nuclear factor kappa beta; protein purification; protein structure function; receptor expression; transcription factor

The goal of this project is to explore the overlapping regulatory programs that control both the reproductive process and aging. This goal will be pursued by following the paradigm of the age-dependent regulation of the rat androgen receptor (rAR) gene in the liver. The hepatic expression of the rAR gene declines more than 70-fold from young-adult (3-month old) to senescent (24-month old) rats. During the previous funding period, we have characterized the rAR gene promoter and identified a number of regulatory elements that can potentially contribute to its age-dependent regulation. These include: 1) A novel positively acting trans-activator called the age-dependent factor (ADF) whose hepatic level declines by 5-to 7-fold during old age; 2) The nuclear factor kappa B (NF-kappa B), a negative regulator of the rAR gene, that undergoes a marked age-dependent increase in the liver; 3) A novel single-strand pyrimidine binding factor (ssPyrBF) which shows about a two-fold increase in the liver of old rats and can potentially interfere with the binding of Sp1 at the homopurine/homopyrimidine region of the rAR promoter; and 4) A negative composite regulatory element involving a DNA-bending protein (designated as androgen receptor repressor factor, ARRF) and the nuclear factor-1 (NF-1) which shows age- dependent alterations in the expression of its component isoforms. The specific aims of this renewal application include: 1) Purification and characterization of ADF and ssPyrBF; 2) Cloning and characterization of the ADF and ssPyrBF cDNAs; 3) Elucidation of the mechanistic basis of NF-1 and ARRF interaction in the down-regulation of the rAR gene; and 4) Examination of the potential role of the CCAAT/enhancer binding protein (C/EBP) in the regulation of the rAR gene and investigation of its functional interaction with NF-kappa B through heterodimerization. Because of the important influence of these transcription factors in the age-dependent regulation of the rAR gene and the well-documented role of C/EBP-NF-kappa B system in the overall management of oxidative stress and inflammation, results of these studies are expected to provide new insights into the molecular basis of the androgen receptor gene regulation in the context of aging.

该项目的目标是探索重叠监管 控制生殖过程和衰老的程序。这个目标 将遵循与年龄相关的范式来追求 肝脏中大鼠雄激素受体（rAR）基因的调节。 这 rAR基因的肝脏表达下降了70多倍 年轻成年（3个月大）到衰老（24个月大）大鼠。 期间 在之前的资助期间，我们已经表征了 rAR 基因启动子和 确定了一些可能潜在的监管要素 有助于其年龄依赖性调节。 其中包括：1）一本小说 积极作用的反式激活因子称为年龄依赖性因子 (ADF) 老年时肝脏水平下降5至7倍； 2) 的 核因子 kappa B (NF-kappa B)，rAR 的负调节因子 基因，肝脏随着年龄的增长而显着增加； 3） 一种新型单链嘧啶结合因子（ssPyrBF），其显示 年老老鼠的肝脏大约增加两倍，并且有可能 干扰 Sp1 在高嘌呤/高嘧啶上的结合 rAR启动子区域； 4）负面综合监管 涉及 DNA 弯曲蛋白（称为雄激素受体）的元件 抑制因子 (ARRF) 和显示年龄的核因子 1 (NF-1) 其组成亚型表达的依赖性改变。 这 本次更新申请的具体目标包括： 1) 纯化和 ADF 和 ssPyrBF 的表征； 2) 克隆和表征 ADF 和 ssPyrBF cDNA； 3）阐明其机制基础 NF-1 和 ARRF 相互作用导致 rAR 基因下调；和 4) 检查CCAAT/增强子结合的潜在作用 蛋白（C/EBP）对rAR基因的调控及研究 它通过异二聚化与 NF-kappa B 发生功能性相互作用。 由于这些转录因子在 rAR 基因的年龄依赖性调节及其有据可查的作用 C/EBP-NF-kappa B 系统在氧化应激整体管理中的作用 和炎症，这些研究结果有望提供新的 深入了解雄激素受体基因的分子基础 老龄化背景下的监管。