GENITALIA OUTGROWTH AND HYPOSPADIAS

生殖器生长和尿道下裂

基本信息

批准号：
9317645
负责人：
Liang Ma
金额：
$ 34.31万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9317645
关键词：
Alleles Androgen Receptor Androgens Awareness Congenital Abnormality Development Embryonic Development Endocrine Disruptors Environmental Risk Factor Etiology Event Exposure to Fibroblast Growth Factor Receptors Foundations Frequencies Future Genes Genetic Genetic Transcription Genital system Genitalia Goals Hand Heart Abnormalities Human Hypospadias Incidence Knockout Mice Knowledge Lead Limb structure Mammals Masculine Mesenchyme Methods Molecular Genetics Molecular Profiling Morphogenesis Mus Mutant Strains Mice Natural regeneration Pathway interactions Pattern Phase Prevention Process Series Signal Pathway Signal Transduction Techniques Testing Tissue Engineering Tissues WNT Signaling Pathway appendage base beta catenin conditional mutant external genitalia fetal gene therapy genetic analysis global health improved in utero in vivo innovation loss of function male malformation mouse model mutant novel prenatal exposure reproductive sex development disorder transcription factor

项目摘要

Abstract Genital malformation including hypospadias represents the second most common male birth defect after cardiac defect. In the past 50 years, hypospadias incidence has doubled along with other male reproductive problems. It is suspected that fetal exposure to endocrine disruptors may have contributed to this increase. However, the etiology of hypospadias is still largely unclear. Both environmental and genetic factors are involved. In fact, our understandings of genital development in general are still very limited. A complete understanding of genetic pathways governing genital development and masculinization and how perturbations of these pathways lead to genital malformations will have immense applications to improve global health. In the past few years, we have performed comprehensive genetic analyses on genital tubercle (GT) development in the mouse and established a conserved genetic pathway (Wnt/β-cateninSp8Fgf8) in regulating body appendage outgrowth, including limbs and external genitalia. Genetic interactions between Wnt and Shh pathways in regulating both genitalia outgrowth and masculinization have also been described. Together, these studies laid the foundation for understanding posterior embryonic development as well as how environmental factors can influence genitalia development and cause hypospadias. Based on these findings, this proposal will continue to use mouse genetics including a series of conditional mutant mice to investigate a novel genetic pathway regulating GT outgrowth. In Aim I, We will characterize several knockout mouse models to build a genetic pathway regulating GT outgrowth and patterning. In Aim II, we will use a novel and highly innovative Split DamID technique to identify in vivo downstream targets of androgen receptor and β-catenin during genital masculinization. Together, these studies should greatly improve our understanding of genitalia development and hypospadias formation. Our long term goal is to use mouse molecular genetics to understand the process of genital development and masculinization and the etiology of genital malformations, such as hypospadias.

抽象的包括尿道下裂在内的生殖器畸形是仅次于尿道下裂的第二常见男性出生缺陷过去 50 年来，尿道下裂的发病率与其他男性生殖系统疾病一样增加了一倍。人们怀疑胎儿接触内分泌干扰物可能是导致这种增加的原因。然而，尿道下裂的病因仍不清楚，环境因素和遗传因素均不清楚。事实上，我们对生殖器发育的总体了解仍然非常有限。了解控制生殖器发育和男性化的遗传途径以及扰动如何这些导致生殖器畸形的途径将在改善全球健康方面具有巨大的应用。在过去的几年里，我们对生殖结节（GT）的发育进行了全面的遗传分析小鼠体内建立了一条保守的调节机体的遗传通路（Wnt/β-cateninSp8Fgf8）附肢生长，包括四肢和外生殖器 Wnt 和 Shh 之间的遗传相互作用。还描述了调节生殖器生长和男性化的途径。这些研究为理解胚胎后发育以及如何发育奠定了基础根据这些发现，环境因素会影响生殖器发育并导致尿道下裂。该提案将继续使用小鼠遗传学，包括一系列条件突变小鼠来研究在目标 I 中，我们将描述几种基因敲除小鼠模型的特征。为了建立调节 GT 生长和模式的遗传途径，在 Aim II 中，我们将使用一种新颖且高度相关的方法。创新的 Split DamID 技术可识别雄激素受体和 β-连环蛋白的体内下游靶标总之，这些研究应该大大提高我们对生殖器的理解。我们的长期目标是利用小鼠分子遗传学来研究发育和尿道下裂的形成。了解生殖器发育和男性化的过程以及生殖器畸形的病因，例如尿道下裂。