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; 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.

项目摘要 性发展疾病（DSD）包括各种先天性疾病 多种表型，例如病毒化，性腺失去障碍以及延迟或没有青春期。此外， 受影响的个体经常遭受次要影响，包括性别烦躁不安和身体问题，例如 生殖细胞肿瘤和生育障碍，例如多囊卵巢综合征或无植物症。 DSD是 在胚胎发生过程中出现并持续存在性的遗传，发育或激素异常 发展到成年。为了更好地了解DSD的病因，RNA结合蛋白在 性别确定是由于它们通过后控制基因表达的功能而进行了研究 转录剪接，翻译控制和mRNA定位。鉴定RNA结合蛋白RNA靶标 表征这些监管关系对于进一步的理解至关重要 调节性别确定。为了研究性别确定和差异化事件，我们的实验室使用 斑马鱼是一种具有高繁殖力和快速外部发育的遗传障碍模型。因此，这个 强大的脊椎动物系统允许表征因生殖必不可少的因素和途径 雌性性腺的发展，成功的生育能力以及建立和维护。这里的目的将 识别保守的基因和机制，当被破坏时，会导致DSD，生育障碍和 人类的癌症。具体而言，该提案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结合的背景下，性别特定的确定和分化 蛋白质及其靶标。此外，这些目标的完成将在遗传的各个方面提供严格的培训 以及基于分子的分析，包括突变体和转基因的产生，表征和验证 斑马鱼线，基因组克隆和显微镜，这将促进我作为成功独立的发展 发育和生殖生物学领域的研究者。