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，这些疾病表现为 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, 受影响的个人往往遭受次要影响，包括性别焦虑症和身体问题，如 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是以下原因的结果 遗传性、发育性或荷尔蒙异常，在胚胎发育过程中出现，并在有性繁殖过程中持续 发育并进入成年期。为了更好地了解DSD的病因，RNA结合蛋白在DSD中的作用 性别决定是由于它们通过后基因表达控制基因表达的功能而被研究的 转录剪接、翻译控制和信使核糖核酸定位。识别RNA结合蛋白RNA靶标 而表征这些调控关系对于我们进一步理解机制是至关重要的 规范性别决定。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，一种遗传易驯化的模型，繁殖力高，外部发育快。因此，这 强大的脊椎动物系统可以描述对生殖至关重要的因素和途径 女性性腺的发育、成功受孕以及建立和维持。本文的目的将是 识别保守的基因和机制，当被破坏时，这些基因和机制会导致DSD、生育障碍和 人类的癌症。具体地说，这项提案的目的将调查监管的因素和机制 在保守的脊椎动物特异性RNA结合的背景下的性别特异性确定和分化 蛋白质及其靶标。此外，完成这些目标将在遗传学的所有方面提供严格的培训 以及基于分子的分析，包括突变和转基因的产生、特征和验证 斑马鱼品系、基因组克隆和显微镜，这些都将促进我作为一个成功的独立人士的发展 发展和生殖生物学领域的研究人员。

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.