HUMAN ANDROGEN RECEPTOR STRUCTURE/FUNCTION

描述(改编自《调查者摘要》)： X染色体AR基因已被确定为潜在的分子 人类雄激素不敏感综合征(AIS)的损害及对 AR结构/功能关系是基于这些自然发生的 突变。本提案的总体目标是了解AR如何 结构/功能，以及影响AR功能的细胞因素， 相互作用以促进AR介导的行动。关于表型的最新数据 异质性表明，AIS包含一套更复杂的监管 影响AR功能的错误。这项研究提案的目标是： 1)确定内源性细胞因素是否影响AR 培养的人生殖器皮肤成纤维细胞的转录活性及PLAY 在性别表型决定中的关键作用；2)识别AR 编码N-末端转录的外显子1的基因突变 AR的激活域(或5‘调控区)来确定 该结构域在AR反式激活和AR基因表达中的功能作用， 分别；3)确定核苷酸(S)及其在一个 新的雄激素受体特异性转录活性反应元件 以及推测的DNA结合域中的氨基酸 与人AR类固醇结合和反式激活的共激活剂； 研究可能的辅激活子与人AR的相互作用 类固醇结合结构域并确定这些相互作用是否被破坏 通过AR的突变。

DESCRIPTION (Adapted from the Investigator's Abstract): Mutations in the X-chromosomal AR gene have been identified as the underlying molecular lesion in human androgen insensitivity syndrome (AIS) and understanding of AR structure/function relationships are based upon these naturally occurring mutations. The overall goal of this proposal is to understand how AR structure/function, and the cellular factors that influence AR function, interact to promote AR-mediated action. Recent data regarding phenotypic heterogeneity suggests that AIS comprises a more complex set of regulatory errors influencing AR function. The goals of this research proposal are: 1) To determine whether endogenous cellular factors influence AR transcriptional activity in cultured human genital skin fibroblasts and play a critical role in the determination of sex phenotype; 2) To identify AR gene mutations within exon 1 encoding the N-terminal transcriptional activation domain of AR(or the 5' regulatory region) to determine the functional role of this domain on AR transactivation and AR gene expression, respectively; 3) To determine the nucleotide (s) and their spacing within a novel androgenreceptor-specific, transcriptionally active response element and the amino acids within the DNA-binding domain of the putative coactivators with the human AR steroid-binding and transactivation; and 4) To characterize the interaction of putative coactivators with the human AR steroid-binding domain and to determine if these interactions are disrupted by mutations in AR.