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 睾丸女性化)，对部分形式的雄激素抵抗(如 作为Reifenstein综合征)，对有证据的个人 男性化不足或不育。到目前为止，大部分信息 关于AR缺陷的研究来自于对大多数 严重影响表型或来自明确的个体 雄激素结合异常。我们对此知之甚少 缺陷会导致不太严重的表型异常， 除了DNA结合域的突变，几乎没有什么是 已知的受体大小变化的机制 结构被转化为AR函数的异常。我们建议 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(部分形式的雄激素 抗性)和基于配基结合分析分类的一种 (质量上正常的配基结合水平正常或降低)；2) 识别与重要的功能片段相互作用的蛋白质 AR。这些实验将包括研究，以证明 相互作用发生在细胞中，识别的蛋白质调节AR 功能；3)进行AR结构相关变化的研究 [AR内的删除或激素中的氨基酸替换- 结合结构域(HBD)]具有AR与DNA结合的能力，经历 翻译后修饰和结合特定的相互作用蛋白。 这些研究的结果将进一步确定AR基因突变 这可能会导致男性化缺陷(特别是当它与 受影响较轻的表型)，并将提供第一个详细的 关于AR突变的机制的信息(S) (氨基酸末端缺失，HBD中的氨基酸替换)原因 AR函数的缺陷。

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.