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: 8458224
• 负责人: Andrew J Pask
• 金额: $ 34.2万
• 依托单位: UNIVERSITY OF CONNECTICUT STORRS
• 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 2013-09-06
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8458224
• 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; 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. PUBLIC HEALTH RELEVANCE: Hypospadias (the abnormal placement of the urethral opening on the penis) is one of the most common birth defects in the USA, affecting approximately 1 in every 140 live male births. Inappropriate exposure to hormones during development has been shown to cause hypospadias and an increase in environmental endocrine disrupting chemicals has been implicated in the doubling in incidence of this disease in the USA between 1970-1993. In this proposal, we will investigate the role of a new long noncoding RNA gene that is necessary for urethral closure and has the potential for hormonal disruption suggesting it could be cause of human sporadic hypospadias.

描述（由申请人提供）：尿道下裂（尿道口位置异常）是美国最常见的出生缺陷之一，大约每140名活产男婴中就有1名受到影响。尽管其发病率很高，但对这种常见疾病的原因知之甚少。一些基因已经被分离出来，使阴茎易患尿道下裂。然而，仅遗传原因不能解释1970-1993年间美国尿道下裂报告率的翻倍。由于不适当的雌激素暴露或雄激素信号传导的抑制都被证明会诱导尿道下裂，其增加已归因于环境因素，环境内分泌干扰物（EEDs）是主要候选者。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这种疾病的临床管理的潜在目标是至关重要的。在这个提议中，我们将定义一个新的长的非编码RNA分子（lnc 353），这是必要的小鼠尿道闭合的功能。lnc 353缺失导致尿道闭合完全失败，导致严重的阴茎阴囊型尿道下裂，反映人类严重尿道下裂表型。我们已经发现lnc 353两侧有多种雄激素和雌激素受体反应元件，这表明它是在激素的直接控制下，是内分泌干扰的潜在靶点。此外，lnc 353在人类基因组中在核苷酸水平（>80%）和其物理位置上都异常高度保守，表明其具有重要的发育功能。在这个提议中，我们将定义lnc 353在尿道闭合中的功能，它与已知和新的阴茎图案网络的相互作用，它的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lnc 353突变是否与人类严重尿道下裂相关。这项工作将描述一个重要的新球员在正常尿道闭合和阴茎发育。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，这些研究是基础。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，预防和治疗研究来改善国家的健康;在人类生长和发育的过程中;以及环境污染物的生物学效应。 公共卫生相关性：尿道下裂（尿道口在阴茎上的异常位置）是美国最常见的出生缺陷之一，每140个活产男婴中就有1个受到影响。在发育过程中不适当地暴露于激素已被证明会导致尿道下裂，并且环境内分泌干扰化学物质的增加与1970-1993年间美国这种疾病的发病率翻了一番有关。在这个提议中，我们将研究一个新的长的非编码RNA基因的作用，该基因是尿道闭合所必需的，并且具有激素干扰的潜力，这表明它可能是人类散发性尿道下裂的原因。