Novel Androgen Receptor Associated Non-coding RNA's

描述(由申请人提供)： 除了雄激素受体，雄激素受体基因AR还编码几个非编码的RNA转录本，雄激素受体是前列腺癌生长的主要调节因素。虽然这些非编码RNA不能翻译成蛋白质产物，但这些RNA本身可以影响AR的转录和/或活性，就像其他非编码RNA已被证明改变蛋白质编码基因的表达一样。我们的总体目标是对新型雄激素受体相关转录本(ARAT)的结构和调控有一个完整的分子理解，以便了解它们在前列腺癌中与AR相关的功能。具体目标是：1)完成人类X染色体上各种ARAT转录本的分子鉴定。这将要求我们：确定Arat RNA转录本的大小、序列和数量，并确定在Arat中是否有任何开放的阅读框架；确定每个Arar的方向是AR的正义还是反义；表征每个Arat的启动子区域和染色质结构；并使用比较基因组学来确定每个Arat的保守的和可能的基本特征；2)表征和量化Arat基因在人类各种组织中的表达；3)确定Arat在体外受雄激素、其他类固醇激素、IGF-I和IGF-II以及其他生长因子调节的前列腺癌细胞的生理调节；4)利用RNA干扰技术通过基因敲除的方法确定每一个ARAT转录本的功能。这些新发现的Arat ncRNAs代表了一组全新的AR相关产物，它们可能为前列腺癌的治疗提供新的靶点。

DESCRIPTION (provided by applicant): The androgen receptor gene AR encodes several noncoding RNA transcripts in addition to the androgen receptor, a major regulator of prostate cancer growth. While these noncoding RNAs are not translated into protein products, the RNAs themselves can act to influence the transcription and/or activity of the AR much as other noncoding RNAs have been shown to alter the expression of protein-coding genes. Our overall goal is to gain a complete molecular understanding of the structure and regulation of the novel androgen receptor-associated transcripts (ARat) in order to learn how they function in relation to the AR in prostate cancer. The specific aims are designed to: 1) complete the molecular characterization of the various ARat transcripts on the human X chromosome. This will require us to: determine the size, sequence and number of ARat RNA transcripts, and determine if there are any open reading frames in the ARat; ascertain whether each ARars orientation is sense or antisense to AR; characterize the promoter region and chromatin structure for each ARat; and use comparative genomics to determine the conserved and presumably essential features of each ARat; 2) characterize and quantify ARat gene expression in various human tissues; 3) determine the physiologic regulation of ARat in prostate cancer cells in vitro as regulated by androgens, other steroid hormones, IGF-I and IGF-II, and other growth factors; and 4) determine the function of each ARat transcript by the method of gene knock-down using RNA interference. These newly discovered ARat ncRNAs represent an entirely novel group of AR-associated products, and they may provide new targets for the treatment of prostate cancer.