Novel Androgen Receptor Associated Non-coding RNA's

描述（由申请人提供）： 雄激素受体基因AR除了编码雄激素受体外，还编码几种非编码RNA转录物，雄激素受体是前列腺癌生长的主要调节因子。虽然这些非编码RNA不翻译成蛋白质产物，但RNA本身可以影响AR的转录和/或活性，就像其他非编码RNA已经显示出改变蛋白质编码基因的表达一样。我们的总体目标是获得对新型雄激素受体相关转录物（Arat）的结构和调节的完整分子理解，以了解它们如何与前列腺癌中的AR相关。具体目标是：1）完成人类X染色体上各种Arat转录本的分子表征。这将要求我们：确定ARat RNA转录物的大小、序列和数量，并确定ARat中是否存在任何开放阅读框;确定每个ARat的方向对AR是有义还是反义;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的保守和可能的基本特征; 2）表征和定量各种人体组织中的ARat基因表达; 3）确定体外前列腺癌细胞中ARat的生理调节，如由雄激素、其它类固醇激素、IGF-I和IGF-II以及其它生长因子调节;和4）通过使用RNA干扰的基因敲低方法确定每个ARat转录物的功能。这些新发现的ARat ncRNA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.