HUMAN ANDROGEN RECEPTOR STRUCTURE/FUNCTION

描述（改编自研究者摘要）： X染色体AR基因已被确定为潜在的分子 雄激素不敏感综合征（AIS）病变及认识 AR结构/功能关系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功能的细胞因子， 相互作用以促进AR介导的作用。关于表型的最新数据 异质性表明，AIS包括一套更复杂的监管机制， 影响AR功能的误差。本研究提案的目标是： 1)确定内源性细胞因子是否影响AR 培养的人生殖器皮肤成纤维细胞的转录活性和作用 在性别表型的决定中起关键作用; 2）鉴定AR 外显子1内编码N-末端转录因子的基因突变 AR的激活结构域（或5'调控区），以确定AR的激活结构域。 该结构域对AR反式激活和AR基因表达的功能作用， 3）为了确定一个或多个核苷酸和它们在一个或多个核苷酸内的间隔， 新的雄激素受体特异性转录活性反应元件 和推定的DNA结合结构域内的氨基酸 与人AR类固醇结合和反式激活的共激活剂;和4） 表征推定的共激活因子与人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中的突变。

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.