Molecular mechanisms of sex-specific differentiation

性别特异性分化的分子机制

• 批准号: 10678628
• 负责人: Miranda Wilson
• 金额: $ 4.75万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-04 至 2026-05-03
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10678628
• 关键词: Adult; Affect; Affinity Chromatography; Binding Sites; Biological Assay; Characteristics; Chromosome 4; Chromosomes; Cloning; Complex; Cytosine; DNA; DNA Methylation; Data; Dedications; Development; Developmental Biology; Drosophila genus; Embryonic Development; Environmental Risk Factor; Etiology; Event; FRAP1 gene; Failure; Female; Fertility; Fertility Disorders; Fostering; Gene Expression; Generations; Genes; Genetic; Genomics; Germ cell tumor; Gonadal Dysgenesis; Gonadal structure; Health; Hormonal; Human; Impairment; Individual; Infertility; Laboratories; Life; Link; Maintenance; Malignant Neoplasms; Mammals; Messenger RNA; Methylation; Methyltransferase; Microscopy; Modeling; Molecular; Mutation; Nutrient availability; Oocytes; Oogenesis; Organism; Ovary; Pathway interactions; Phenotype; Polycystic Ovary Syndrome; Premature Ovarian Failure; Proteins; Puberty; RNA; RNA Binding; RNA Splicing; RNA-Binding Proteins; Regulation; Reiterated Genes; Reporter; Repression; Reproductive Biology; Reproductive Health; Research Personnel; Ribosomal DNA; Ribosomes; Role; Sex Chromosomes; Sex Differentiation; Sexual Development; Signal Transduction; Spermatogenesis; System; Testing; Testis; Training; Transcript; Transgenic Organisms; Translations; Validation; Vertebrates; Virilism; Y Chromosome; Zebrafish; autosome; detection of nutrient; gender dysphoria; gene conservation; gene product; genetic approach; gonad development; hormonal signals; insight; male; methylation pattern; mutant; nutrition; ovarian failure; posttranscriptional; preservation; programs; reproductive development; reproductive fitness; sex; sex determination; sex development disorder; translation factor

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.

项目概要 性发育障碍 (DSD) 包括多种先天性疾病，表现为 不同的表型，例如男性化、性腺发育不全以及青春期延迟或缺失。此外， 受影响的个人通常会遭受继发性影响，包括性别不安和身体问题，例如 生殖细胞肿瘤和生育障碍，如多囊卵巢综合征或无精症。 DSD 的结果是 在胚胎发生过程中出现并在整个性过程中持续存在的遗传、发育或激素异常 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 由于它们通过后处理控制基因表达的功能，性别决定已被研究 转录剪接、翻译控制和 mRNA 定位。鉴定 RNA 结合蛋白 RNA 靶标 描述这些监管关系对于进一步理解机制至关重要 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，一种具有高繁殖力和快速外部发育的遗传易驯化模型。因此，这 强大的脊椎动物系统可以表征生殖所必需的因素和途径 发育、成功生育以及女性性腺的建立和维持。本文的目标将 识别保守的基因和机制，当它们被破坏时，会导致 DSD、生育障碍和 人类癌症。具体来说，该提案的目的是调查调节因素和机制 保守脊椎动物特异性 RNA 结合背景下的性别特异性决定和分化 蛋白质及其靶标。此外，这些目标的完成将为遗传的各个方面提供严格的培训。 和基于分子的分析，包括突变体和转基因的生成、表征和验证 斑马鱼系、基因组克隆和显微镜检查，这将促进我作为一名成功的独立科学家的发展 发育和生殖生物学领域的研究员。