Molecular mechanisms of sex-specific differentiation

项目摘要 性发育障碍（DSD）包括各种先天性疾病， 不同的表型，如男性化、性腺发育不全和青春期延迟或缺失。此外，本发明还提供了一种方法， 受影响的个人往往遭受二次影响，包括性别焦虑和身体问题， 生殖细胞肿瘤和生育障碍，如多囊卵巢综合征或无精子症。DSD是以下因素的结果： 在胚胎发育过程中出现的遗传、发育或激素异常，并在整个性生活中持续存在。 发展到成年。为了更好地了解DSD的病因，RNA结合蛋白在 性别决定已被研究，由于它们的功能，控制基因的表达，通过后， 转录剪接、翻译控制和mRNA定位。识别RNA结合蛋白RNA靶标 描述这些调节关系对于我们进一步理解 调节性别决定。为了研究性别决定和分化的事件，我们的实验室使用 斑马鱼，一种遗传上易于控制的模式，具有高繁殖力和快速的外部发育。因此本 强大的脊椎动物系统允许表征的因素和途径是必不可少的生殖 发育、成功生育以及雌性性腺的建立和维持。本文的目标将 确定保守基因和机制，当被破坏时，有助于DSD，生育障碍， 人类的癌症具体而言，本建议的目的将调查调节的因素和机制， 在保守的脊椎动物特异性RNA结合背景下的性别特异性决定和分化 蛋白质及其靶点此外，完成这些目标将提供严格的培训，在所有方面的遗传 和基于分子的分析，包括突变体和转基因的产生、表征和验证 斑马鱼系，基因组克隆和显微镜，这将促进我作为一个成功的独立的发展 发育和生殖生物学领域的研究者。

Project Summary Disorders of sexual development (DSDs) encompass a variety of congenital conditions that present with diverse phenotypes, such as virilization, gonadal dysgenesis, and delayed or absent puberty. In addition, affected individuals often suffer from secondary effects, including gender dysphoria and physical issues such as germ cell tumors and fertility disorders like polycystic ovarian syndrome or azoospermia. DSDs are the result of genetic, developmental, or hormonal anomalies that arise during embryogenesis and persist throughout sexual development and into adulthood. To better understand the etiology of DSDs, the role of RNA binding proteins in sex determination has been investigated due to their functions in controlling gene expression via post- transcriptional splicing, translational control, and mRNA localization. Identifying RNA binding protein RNA targets and characterizing these regulatory relationships is essential to further our understanding of mechanisms regulating sex determination. To study the events of sex determination and differentiation, our laboratory uses zebrafish, a genetically tractable model with high fecundity and rapid external development. Therefore, this powerful vertebrate system allows characterization of factors and pathways that are essential to reproductive development, successful fertility, and establishment and maintenance of the female gonad. The aims herein will identify conserved genes and mechanisms, that when disrupted, contribute to DSDs, fertility disorders, and cancers in humans. Specifically, the aims of this proposal will investigate the factors and mechanisms regulating sex-specific determination and differentiation in the context of a conserved vertebrate specific RNA binding protein and its targets. Further, completion of these aims will provide rigorous training in all aspects of genetic and molecular-based analyses, including generation, characterization, and validation of mutant and transgenic zebrafish lines, genomic cloning, and microscopy, which will foster my development as a successful independent investigator in the fields of developmental and reproductive biology.