New Players in Urethral Closure; Defining the Role of a Novel Long Noncoding RNA

描述(由申请人提供)：尿道下裂(尿道口的异常位置)是美国最常见的出生缺陷之一，大约每140名男性活产中就有一名受到影响。尽管发病率很高，但人们对这种常见疾病的病因知之甚少。已分离出几个使阴茎易患上尿道下裂的基因。然而，仅靠遗传因素并不能解释1970-1993年间美国报告的尿道下裂发病率翻倍的原因。由于不适当的雌激素暴露或雄激素信号的抑制都被证明会导致尿道下裂，因此它的增加被归因于环境因素，其中环境内分泌干扰物(EEDs)是主要的候选因素。因此，了解激素和调节尿道闭合的关键分子通路之间的相互作用对于确定尿道下裂的原因和临床治疗的潜在靶点是至关重要的。在这项提案中，我们将定义一种新的长非编码RNA分子(Lnc353)的功能，它是小鼠关闭尿路所必需的。缺失lnc353会导致完全失败的尿道闭合，导致严重的阴囊下裂，这反映了人类严重的尿道下裂的表型。我们已经证明，LNC353的两侧有多种雄激素和雌激素受体反应元件，这表明它受到激素的直接控制，是内分泌干扰的潜在靶点。此外，在人类基因组中，Lnc353在核苷酸水平(80%)和其物理位置上都高度保守，这表明它具有重要的发育功能。在这项提案中，我们将定义lnc353在尿道闭合中的功能，它与已知的和新的阴茎模式网络的相互作用，它的激素控制和内分泌干扰的可能性。在未来的工作中，我们将确定lnc353基因突变是否与人类严重的尿道下裂有关。这项工作将描述一个在正常的尿路闭合和阴茎发育中起关键作用的新角色。我们的发现将提供关于这种常见疾病的遗传和激素原因的迫切需要的信息，并有助于开发诊断和治疗这种疾病的新方法。在我们评估这种疾病的临床治疗和近几十年来尿道下裂发病率急剧增加的潜在原因之前，这些研究是基本的。这项研究符合美国国立卫生研究院的使命，特别是通过开展和支持关于人类疾病的起因、诊断、预防和治疗、人类生长和发育过程以及环境污染物的生物影响的研究来改善国家的健康。

DESCRIPTION (provided by applicant): Hypospadias (the abnormal placement of the urethral opening) is one of the most common birth defects in the USA, affecting approximately 1 in every 140 live male births. Despite its high incidence, relatively little is known about the causes of this common disease. A few genes have been isolated that predispose the penis to hypospadias. However, genetic causes alone cannot explain a doubling in the reported rate of hypospadias in the USA between 1970-1993. Since inappropriate estrogen exposure or inhibition of androgen signaling have both been shown to induce hypospadias, its increase has been attributed to environmental factors, with environmental endocrine disruptors (EEDs) being prime candidates. Thus, understanding the interplay between hormones and the critical molecular pathways regulating urethral closure is essential to define the causes of hypospadias and potential targets for the clinical management of this disease. In this proposal we will define the function of a novel long noncoding RNA molecule (lnc353) that is necessary for urethral closure in mice. Deletion of lnc353 causes a complete failure of urethral closure resulting in a severe penoscrotal hypospadias, mirroring human severe hypospadias phenotypes. We have shown that lnc353 is flanked by multiple androgen and estrogen receptor response elements suggesting it is under direct hormonal control and a potential target of endocrine disruption. Furthermore, lnc353 is unusually highly conserved in the human genome both at the nucleotide level (>80%) and in its physical location, suggesting an important developmental function. In this proposal we will define the function of lnc353 in urethral closure, its interaction with know and novel penile patterning networks, its hormonal control and potential for endocrine disruption. In future work, we will determine if mutations in lnc353 are associated with severe hypospadias in humans. This work will characterize a critical new player in normal urethral closure and penile development. Our findings will provide much needed information on the genetic and hormonal causes of this common disease and aid in the development of new ways to diagnose and treat this condition. Such studies are fundamental before we can assess clinical management of this disease and the potential reasons for the dramatic increase in hypospadias incidence over recent decades. This research is inline with the missions of the NIH, specifically by Improving the health of the Nation by conducting and supporting research in the causes, diagnosis, prevention, and cure of human diseases; in the processes of human growth and development; and in the biological effects of environmental contaminants.