Dissecting the Genetic and Cellular Mechanisms of Urethral Tube Defects

项目摘要/摘要 下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，特征是尿管闭合失败和 包皮(包皮)和腹侧阴茎的不完全形成--估计每250人中就有1人受到影响 出生。受影响的儿童可能有超大或多个尿道口，以及严重的尿路下裂 生来就有不明确的生殖器。除了最轻微的形式外，所有的形式都需要手术干预。该病的病因学 尿道下裂尚不清楚，但最近在受影响的个体中发现了拷贝数变异(CNV) 提示尿路下裂易感性增加的遗传基础，暴露于 环境内分泌干扰物(EDCs)。我们对最基本的分子的有限知识 生殖器结节的形成机制一直是理解尿管如何 在正常发育过程中形成的，如何发生的，以及内分泌细胞如何影响基因调控 协调外生殖器发育的网络(GRN)。我们的小组之前显示了删除 成纤维细胞生长因子受体-2(FGFR2)导致小鼠的尿道下裂，最近的研究表明 通过确定影响FGFR2基因座的缺失，这一发现在翻译上的重要性 尿道管缺陷。在这个项目中，我们的目标是确定FGFR2协调尿路的机制 管子编队。具体目标1的目标是通过以下方式了解尿路发育的遗传控制 解剖FGFR2 GRN以确定下游靶点并阐明其功能。具体的目标 目的2是了解FGFR2如何调控驱动尿路小管形成的细胞过程。这些 目标将通过整合发育遗传学、细胞生物学和新型转基因来实现。 老鼠模型。通过将鼠标数据直接与 已知CNV的尿道下裂人类病例，这将在突变之间建立机制联系 男童尿路结构缺陷的基因分型和表型。

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.