Dissecting the Genetic and Cellular Mechanisms of Urethral Tube Defects

剖析尿道管缺陷的遗传和细胞机制

• 批准号: 9312264
• 负责人: MARTIN J COHN
• 金额: $ 33.22万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9312264
• 关键词: Affect; Alleles; Anatomy; Apical; Behavior Control; Cell Adhesion; Cell Polarity; Cell Shape; Cell division; Cell physiology; Cell-Matrix Junction; Cells; Cellular biology; Child; Clinical Research; Complex; Congenital Abnormality; Copy Number Polymorphism; Cues; Data; Defect; Development; Developmental Process; Endocrine Disruptors; Environment; Epithelial Cells; Epithelium; Etiology; Exposure to; FGFR2 gene; Failure; Feedback; Fibroblast Growth Factor Receptor 2; Genes; Genetic; Genital system; Genitourinary system; Genomics; Genotype; Goals; Human; Hypospadias; Individual; Instruction; Knowledge; Lead; Link; Live Birth; Mediating; Molecular; Molecular Genetics; Morphogenesis; Mus; Mutation; Operative Surgical Procedures; Organ; Outcome; Pathway interactions; Patients; Pattern; Phenocopy; Phenotype; Predisposition; Prevention; Prevention strategy; Regulation; Regulator Genes; Role; SHH gene; Series; Signal Transduction; Simple Epithelium; Stratification; Structural defect; Testing; Tissues; Transgenic Mice; Translating; Tube; Tubular formation; Urethra; Urologic Diseases; ambiguous genitalia; boys; design; developmental genetics; external genitalia; gastrulation; malformation; mouse model; mutant; novel; penis; penis foreskin; prenatal exposure; prepuce; programs; transcription factor; translational impact

PROJECT SUMMARY/ABSTRACT Malformations of the lower genitourinary tract are among the most common birth defects in humans. Hypospadias -- a malformation of the external genitalia characterized by failure of urethral tube closure and incomplete formation of the prepuce (foreskin) and ventral penis -- affects an estimated 1 of every 250 live births. Affected children can have oversized or multiple urethral openings, and those with severe hypospadias are born with ambiguous genitalia. All but the mildest forms require surgical intervention. The etiology of hypospadias is not understood, but recent discoveries of copy number variations (CNVs) in affected individuals suggest a genetic basis for increased susceptibility to hypospadias, which may be compounded by exposure to environmental endocrine disrupting chemicals (EDCs). Our limited knowledge of the most basic molecular mechanisms that pattern the genital tubercle has been an obstacle to understanding how the urethral tube forms during normal development, how hypospadias arises, and how EDCs can affect the gene regulatory networks (GRNs) that orchestrate external genital development. Our group previously showed that deletion of Fibroblast growth factor receptor-2 (Fgfr2) causes hypospadias in mice, and recent studies have illustrated the translational importance of this discovery by identifying deletions affecting the FGFR2 locus in boys with urethral tube defects. In this project, we aim to identify the mechanisms by which Fgfr2 orchestrates urethral tube formation. The goal of Specific Aim 1 is to understand the genetic control of urethra development by dissecting the Fgfr2 GRN to identify downstream targets and to elucidate their functions. The goal of Specific Aim 2 is to understand how Fgfr2 regulates the cellular processes that drive urethral tubulogenesis. These objectives will be accomplished by integrating developmental genetics, cell biology, and novel transgenic mouse models. An immediate translational impact will come through direct comparison of the mouse data to human cases of hypospadias with known CNVs, which will establish the mechanistic links between mutant genotypes and the phenotypes of boys with structural defects of the urethra.

项目总结/摘要 下泌尿生殖道畸形是人类最常见的出生缺陷之一。 尿道下裂--一种外生殖器畸形，其特征是尿道管闭合失败， 包皮（包皮）和腹侧阴茎的不完全形成-估计每250个活的人中就有1个受到影响 出生受影响的儿童可以有过大或多个尿道口， 出生时生殖器不明确除了最轻微的形式外，所有形式都需要手术干预。的病因 尿道下裂是不了解，但最近发现的拷贝数变异（CNVs），在受影响的个人 表明尿道下裂易感性增加的遗传基础，这可能是由于暴露于 环境内分泌干扰物（EDCs）。我们对最基本分子的有限知识 生殖器结节的形成机制一直是理解尿道管如何 在正常发育过程中形成，尿道下裂是如何发生的，以及内分泌干扰物如何影响基因调控。 网络（GRNs）协调外部生殖器发育。我们的研究小组先前表明， 成纤维细胞生长因子受体2（Fgfr 2）导致小鼠尿道下裂，最近的研究表明， 这一发现的翻译重要性，通过鉴定影响FGFR 2基因座的缺失，在男孩， 尿道管缺损在这个项目中，我们的目标是确定Fgfr 2协调尿道的机制， 管形成具体目标1的目标是通过以下方式了解尿道发育的遗传控制 剖析Fgfr 2 GRN以识别下游靶点并阐明其功能。具体目标 目的2是了解Fgfr 2如何调节驱动尿道小管形成的细胞过程。这些 目标将通过整合发育遗传学，细胞生物学和新的转基因技术来实现。 小鼠模型。通过直接比较小鼠数据， 已知CNVs的尿道下裂人类病例，这将建立突变体之间的机制联系， 基因型和表型的男孩与尿道结构缺陷。