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: 9159586
• 负责人: MARTIN J COHN
• 金额: $ 33.24万
• 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/9159586
• 关键词: Affect; Anatomy; Apical; Behavior Control; Boxing; 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; Genetic Programming; 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; base; boys; design; developmental genetics; external genitalia; gastrulation; malformation; mouse model; mutant; novel; penis; penis foreskin; prenatal exposure; prepuce; programs; transcription factor

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.

项目概要/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和 包皮（包皮）和阴茎腹侧形成不完全——估计每 250 名活人中就有 1 人受到影响 出生。受影响的儿童可能有过大或多个尿道开口，以及患有严重尿道下裂的儿童 生来就有不明确的生殖器。除最轻微的形式外，所有形式都需要手术干预。病因学 尿道下裂尚不清楚，但最近在受影响个体中发现了拷贝数变异 (CNV) 表明尿道下裂易感性增加有遗传基础，这可能因暴露于 环境内分泌干扰化学物质（EDC）。我们对最基本的分子知识有限 生殖器结节的形成机制一直是理解尿道管如何形成的障碍 正常发育过程中的形成、尿道下裂如何发生以及 EDC 如何影响基因调控 协调外生殖器发育的网络（GRN）。我们小组之前表明删除 成纤维细胞生长因子受体 2 (Fgfr2) 会导致小鼠尿道下裂，最近的研究表明 通过鉴定影响男孩 FGFR2 基因座的缺失，了解这一发现的翻译重要性 尿道管缺陷。在这个项目中，我们的目标是确定 Fgfr2 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 Fgfr2 GRN 以识别下游靶点并阐明其功能。具体目标 目标 2 是了解 Fgfr2 如何调节驱动尿道小管发生的细胞过程。这些 目标将通过整合发育遗传学、细胞生物学和新型转基因来实现 鼠标模型。通过直接比较小鼠数据和 具有已知 CNV 的人类尿道下裂病例，这将建立突变体之间的机制联系 具有尿道结构缺陷的男孩的基因型和表型。