ACTION OF HORMONES ON PROTEIN AND RNA METABOLISM

雄激素受体（AR）缺陷导致一系列表型 从完全雄激素抵抗（完全性 睾丸女性化），部分形式的雄激素抵抗（如 作为赖芬斯坦综合征），对有证据表明 男性化不足或不育。迄今为止， 关于AR缺陷的研究来自于对患有最严重AR缺陷的患者的研究。 严重受影响的表型或来自具有明显 雄激素结合异常。关于这一点，我们所知甚少。 缺陷导致不太严重的表型异常， 除了DNA结合结构域的突变，几乎没有什么是 已知的机制，通过大或小的变化受体 结构转化为AR功能异常。我们提出 在三个相关领域进行实验：1）AR缺陷将 定义为两组：一组表型（雄激素的部分形式 抗性）和一种基于通过配体结合测定的分类 （正常或降低水平的定性正常配体结合）; 2） 鉴定与蛋白质的功能重要片段相互作用的蛋白质 的AR。这些实验将包括研究，以证明 相互作用发生在细胞中，并且所鉴定的蛋白质调节AR 功能; 3）进行研究以关联AR结构的改变 [AR内的缺失或激素中的氨基酸取代- 结合结构域（HBD）]与AR结合DNA的能力，经历 翻译后修饰并结合特异性相互作用蛋白。 这些研究结果将进一步明确AR基因突变 这可能会导致男性化的缺陷（特别是当它涉及到 不太严重的影响表型），并将提供第一个详细的 关于AR突变的机制的信息 （氨基末端缺失，HBD中的氨基酸取代）导致 AR功能缺陷。

Defects in the androgen receptor (AR) cause a spectrum of phenotypic abnormalities ranging from complete androgen resistance (complete testicular feminization), to partial forms of androgen resistance (such as Reifenstein syndrome), to individuals with evidence of undervirilization or infertility. To date, much of the information regarding AR defects has come from studies of patients with the most severely affected phenotypes or from individuals with clearcut abnormalities of androgen binding. Much less is known regarding the defects causing the less severe phenotypic abnormalities and, with the exception of mutations in the DNA-binding domain, virtually nothing is known of the mechanisms by which large or small changes of receptor structure are translated into abnormalities of AR function. We propose to conduct experiments in three related areas: 1) The AR defect will be defined in two groups: one phenotypic (partial forms of androgen resistance) and one based on categorization by ligand-binding assays (normal or reduced levels of qualitatively normal ligand binding); 2) Identify proteins that interact with functionally important segments of the AR. These experiments will include studies to demonstrate that the interactions occur in cells and that the proteins identified modulate AR function; 3) Conduct studies to correlate alterations of AR structure [deletions within the AR or amino acid substitutions in the hormone- binding domain (HBD)] with the capacity of the AR to bind to DNA, undergo posttranslational modifications and bind specific interacting proteins. The results of these studies will further define the AR gene mutations that can cause defects of virilization (particularly as it pertains to less severely affected phenotypes) and will provide the first detailed information regarding the mechanism(s) by which mutations in the AR (amino terminal deletions, amino acid substitutions in the HBD) cause defects of AR function.