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

尿道闭合术的新玩家；

• 批准号: 8543728
• 负责人: Andrew J Pask
• 金额: $ 22.49万
• 依托单位: UNIVERSITY OF MELBOURNE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-30 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8543728
• 关键词: Abdomen; Address; Affect; Agonist; Alternative Splicing; Androgen Receptor; Androgens; Binding Proteins; Biological; Biological Assay; Birth; Chromatin Structure; Clinical Management; Congenital Abnormality; Defect; Development; Diagnosis; Disease; Endocrine; Endocrine Disruptors; Endocrine disruption; Environmental Pollution; Environmental Risk Factor; Epithelium; Estrogen Receptors; Estrogens; Etiology; Exposure to; Failure; Fetus; Fibroblasts; Future; Gene Proteins; Genes; Genetic; Genital system; Growth and Development function; Health; Healthcare; Healthcare Systems; Hormonal; Hormones; Human; Human Genome; Hypospadias; Incidence; Inguinal Hernia; Life; Location; Mediating; Methods; Mission; Molecular; Mus; Mutation; Nucleotides; Operative Surgical Procedures; Pathway interactions; Patients; Pattern; Phenotype; Positioning Attribute; Prevalence; Prevention; Process; Protein Binding; RNA; Reporting; Research; Research Support; Response Elements; Role; Severities; Signal Transduction; Techniques; Testis; Testosterone; Time; Transcript; Transcriptional Regulation; Translating; United States National Institutes of Health; Untranslated RNA; Urethra; Work; care burden; cost; deep sequencing; design; established cell line; hormone regulation; human disease; improved; male; morphogens; next generation; novel; penis; programs; research study

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.

描述（由申请人提供）：尿道下裂（尿道开口位置异常）是美国最常见的出生缺陷之一，大约每 140 名活产男性新生儿中就有 1 人患有尿道下裂。尽管发病率很高，但人们对这种常见疾病的原因知之甚少。已经分离出一些使阴茎易患尿道下裂的基因。然而，仅靠遗传原因无法解释 1970 年至 1993 年间美国尿道下裂发病率翻倍的原因。由于雌激素暴露不当或雄激素信号传导抑制均已被证明会诱发尿道下裂，因此尿道下裂的增加归因于环境因素，其中环境内分泌干扰物（EED）是主要候选者。因此，了解激素与调节尿道闭合的关键分子途径之间的相互作用对于确定尿道下裂的原因和该疾病临床治疗的潜在目标至关重要。在本提案中，我们将定义一种新型长非编码 RNA 分子 (lnc353) 的功能，该分子是小鼠尿道闭合所必需的。 lnc353的缺失导致尿道闭合完全失败，导致严重的阴茎阴囊尿道下裂，反映了人类严重尿道下裂的表型。我们已经证明，lnc353 两侧有多个雄激素和雌激素受体反应元件，表明它受到直接激素控制，并且是内分泌干扰的潜在目标。此外，lnc353 在人类基因组中在核苷酸水平 (>80%) 和物理位置上都异常高度保守，表明其具有重要的发育功能。在本提案中，我们将定义 lnc353 在尿道闭合中的功能、其与已知和新颖的阴茎模式网络的相互作用、其激素控制和内分泌干扰的潜力。在未来的工作中，我们将确定 lnc353 突变是否与人类严重尿道下裂有关。这项工作将描述正常尿道闭合和阴茎发育中关键的新参与者的特征。我们的研究结果将提供有关这种常见疾病的遗传和激素原因的急需信息，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以及近几十年来尿道下裂发病率急剧增加的潜在原因之前，此类研究至关重要。这项研究符合 NIH 的使命，特别是通过开展和支持人类疾病的原因、诊断、预防和治疗方面的研究来改善国家的健康；在人类成长和发展的过程中；以及环境污染物的生物效应。