AGING AND ANDROGEN RECEPTOR GENE REGULATION

衰老与雄激素受体基因调控

• 批准号: 6137038
• 负责人: ARUN K. ROY
• 金额: $ 24万
• 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/6137038
• 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的监管 控制生殖过程和衰老的程序。这个目标 将通过遵循依赖于年龄的范式来追求 肝脏中大鼠雄激素受体(RAR)基因的调节。这个 RAR基因在肝脏中的表达从 幼年-成年(3月龄)至衰老(24月龄)大鼠。在.期间 在之前的资助期间，我们已经表征了RAR基因启动子和 确定了许多可能会 有助于其依赖年龄的监管。其中包括：1)一部小说 称为年龄依赖因子(ADF)的正向作用反式激活剂 其肝脏水平在老年时下降5至7倍；2) 核因子-kappaB--RAR的负性调节因子 基因，在肝脏中经历明显的年龄依赖性增加；3) 一种新的单链嘧啶结合因子(SsPyrBF) 老年大鼠的肝脏大约增加了两倍，并且有可能 干扰Sp1与高嘌呤/高嘧啶的结合 RAR启动子的区域；以及4)负的复合调控 涉及DNA弯曲蛋白(称为雄激素受体)的元件 抑制因子，ARRF)和核因子-1(核因子-1)，这表明年龄- 其组成异构体表达的依赖变化。这个 本次续展申请的具体目标包括：1)提纯和 ADF和ssPyrBF的特性；2)克隆和鉴定 ADF和ssPyrBF的cDNA；3)阐明ADF和ssPyrBF的机制基础 核因子-1和ARRF在RAR基因下调中的相互作用；以及 4)研究CCAAT/增强子结合的潜在作用 蛋白(C/EBP)在RAR基因调控中的作用及其机制研究 它通过异源二聚作用与核因子-kappaB发生功能相互作用。 由于这些转录因子在基因转录中的重要作用 RAR基因的年龄依赖性调节及其已有文献记载的作用 C/EBP-核因子-kappaB系统在氧化应激综合管理中的作用 和炎症，这些研究的结果有望提供新的 对雄激素受体基因分子基础的洞察 老龄化背景下的监管。