AGING AND ANDROGEN RECEPTOR GENE REGULATION

本项目的目标是探索重叠监管 控制生殖过程和衰老的程序。这一目标 将遵循年龄依赖的范式， 调节大鼠肝脏中的雄激素受体（rAR）基因。 的 rAR基因的肝脏表达从2000年开始下降超过70倍。 成年（3月龄）至衰老（24月龄）大鼠。 期间 在上一个资助期，我们已经表征了rAR基因启动子， 确定了一些监管要素， 有助于其年龄依赖性调节。 （1）一部小说 一种称为年龄依赖因子（ADF）的正性反式激活因子 其肝脏水平在老年期间下降5至7倍; 2） 核因子κ B（NF-κ B B），rAR的负调节因子 基因，在肝脏中经历显著的年龄依赖性增加; 3） 一种新的单链嘧啶结合因子（ssPyrBF）， 在老年大鼠的肝脏中大约增加了两倍， 干扰Sp1在高嘌呤/高嘧啶处的结合 rAR启动子区域;和4）负复合调控 一种涉及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（NF-1），其显示年龄- 其组分同种型表达的依赖性改变。 的 该更新申请的具体目的包括：1）纯化和 2）ADF和ssPyrBF的克隆和表征 ADF和ssPyrBF cDNA; 3）阐明ADF和ssPyrBF cDNA的机制基础。 NF-1和ARRF在rAR基因下调中的相互作用;以及 4)检查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， 其通过异源二聚化与NF-κ B功能性相互作用。 由于这些转录因子在转录过程中的重要影响， rAR基因的年龄依赖性调节和充分记录的作用 C/EBP-NF-κ B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 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。

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.