Hypospadias: Morphogenesis of the Proximal Urethra

尿道下裂：近端尿道的形态发生

• 批准号: 8254202
• 负责人: Christine E Larkins
• 金额: $ 4.92万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8254202
• 关键词: Actins; Address; Affect; Androgens; Apoptosis; Area; Biological Models; Birth; Cell Adhesion; Cells; Clitoris; Congenital Abnormality; Data; Defect; Development; Ear; Embryo; Endocrine Disruptors; Endoderm; Environmental Exposure; Epithelial; Epithelium; Event; Extracellular Matrix; Failure; Female; Gene Expression; Gene Mutation; Generations; Genetic; Genital system; Human; Hypospadias; Incidence; Knowledge; Lateral; Lead; Live Birth; Male Genital Organs; Mammals; Mesoderm; Modeling; Molecular; Morphogenesis; Mus; Operative Surgical Procedures; Pattern Formation; Play; Reptiles; Research; Role; Side; Signal Transduction; Slide; Staging; Structure; Surface Ectoderm; Swelling; Tube; Turtles; Urethra; Vagina; Vertebrates; Work; base; comparative; external genitalia; insight; male; malformation; meetings; method development; mutant; novel; penis; prevent; research study

DESCRIPTION (provided by applicant): Hypospadias is a congenital defect characterized by an ectopic opening of the urethra on the ventral side of the penis. It is one of the most common birth defects in males with an incidence of 1 in 125 live births. Currently, the only treatment for hypospadias is surgery. The high incidence of hypospadias is reflective of its multiple causes. Studies have found that environmental exposure of embryos to endocrine disrupting chemicals increases the rate of hypospadias. Additionally, there are syndromic forms of hypospadias that result from genetic mutations. However, in spite of recent progress in understanding external genitalia development it is still not clear exactly how genetic or environmental signals are influencing external genitalia development. The urethra is formed from a plate of endodermally derived epithelium that is surrounded by the mesoderm of the developing external genitalia, or genital tubercle (GT). The urethral plate epithelium cavitates to form the urethral tube, and failure to maintain the integrity of this tube leads to hypospadias. During development of the GT, an ectodermal opening at the base of the GT exposes the underlying urethral tube and occurs in both male and female embryos, but this proximal urethral opening (puo) is closed at later stages in males while it is maintained in females to become the vaginal opening. Interestingly, many cases of hypospadias occur in the proximal penis leading to the hypothesis that defective morphogenesis of the puo causes proximal hypospadias. To address this hypothesis, this proposal will utilize three complimentary approaches. Aim 1 of this proposal will examine the cellular events that control normal formation and closure of the puo during development of the male mouse GT. Aim 2 will address molecular control of puo morphogenesis through examination of changes in gene expression and cellular events in Bmp2 and Fgfr2 mutants. Both Bmp2 and Fgfr2 are expressed in the puo region, and Fgfr2 mutants show defective puo morphogenesis. Finally, Aim 3 will examine the cellular and molecular mechanisms that lead to the naturally occurring open urethra in the red-eared slider turtle Trachemys scripta. This aim will allow for the identification of novel mechanisms important for maintaining urethral closure. Findings from this proposal will not only add to the knowledge of how external genitalia normally develop, but will also identify mechanisms that lead to the generation of hypospadias. This could have broader implications in the development of methods to prevent hypospadias. Additionally, work in T. scripta will aid in determining factors that are involved in the generatio of hypospadias and may lead to a novel model system for studying hypospadias in ovo. PUBLIC HEALTH RELEVANCE: Hypospadias, a defect in urethral tube closure, is one of the most common birth defects occurring in 1 in 125 male births; however, the cause of hypospadias is not clear. This proposal will examine morphogenesis of the proximal urethral opening, a structure that forms in both males and females, but is normally closed at later stages in males. As defective closure of the proximal urethral opening would lead to hypospadias in males, this research will provide insight into the molecular and cellular mechanisms that lead to hypospadias in the proximal urethra.

描述（由申请人提供）：尿道下裂是一种先天性缺陷，其特征是阴茎腹侧的尿道异位开口。它是男性最常见的出生缺陷之一，发病率为1/125活产。目前，唯一的治疗 尿道下裂是外科手术尿道下裂的高发病率反映了其多种原因。研究发现，胚胎暴露于环境中的内分泌干扰化学物质会增加尿道下裂的发病率。此外，还有尿道下裂的综合征形式，由基因突变引起。然而，尽管最近在外生殖器发育方面取得了进展，但仍不清楚遗传或环境信号如何影响外生殖器发育。 尿道由内胚层来源的上皮板形成，所述内胚层来源的上皮板被发育中的外生殖器或生殖结节（GT）的中胚层包围。尿道板上皮形成空洞形成尿道管，如果不能保持尿道管的完整性，就会导致尿道下裂。在GT的发育过程中，GT基部的外胚层开口暴露下面的尿道管，并且在男性和女性胚胎中都发生，但是这个近端尿道开口（puo）在男性的后期阶段关闭，而在女性中保持成为阴道开口。有趣的是，许多尿道下裂病例发生在近端阴茎，这导致了一种假说，即近端尿道下裂是由PU的形态发生缺陷引起的。为了解决这一假设，本提案将采用三种互补的办法。本提案的目的1将检查细胞事件，控制正常形成和关闭的poo在发展过程中的雄性小鼠GT。目的2将通过检查Bmp 2和Fgfr 2突变体的基因表达和细胞事件的变化，解决poo形态发生的分子控制。Bmp 2和Fgfr 2都在poo区域表达，Fgfr 2突变体显示poo形态发生缺陷。最后，目标3将研究导致红耳滑龟Trachemys scripta自然发生开放尿道的细胞和分子机制。这一目标将允许识别新的机制，重要的是保持尿道闭合。 这项研究的发现不仅将增加外生殖器正常发育的知识，而且还将确定导致尿道下裂的机制。这可能对预防尿道下裂的方法的发展产生更广泛的影响。此外，在T. scripta将有助于确定尿道下裂发生的相关因素，并可能为研究卵内尿道下裂提供新的模型系统。 公共卫生相关性：尿道下裂是一种尿道管闭合缺陷，是最常见的出生缺陷之一，每125名男性中就有1名发生;然而，尿道下裂的原因尚不清楚。这个建议将研究近端尿道口的形态发生，这是一种在男性和女性中都形成的结构，但在男性的后期阶段通常是闭合的。由于近端尿道口闭合不良会导致男性尿道下裂，因此本研究将为深入了解导致近端尿道下裂的分子和细胞机制提供帮助。