Germ Cell Differentiation from Human Embryonic Stem Cells

生殖细胞从人类胚胎干细胞分化

• 批准号: 7315907
• 负责人: LINDA C GIUDICE
• 金额: --
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7315907
• 关键词: Address; Adhesions; Affect; Animal Model; Assisted Reproductive Techniques; Assisted Reproductive Technology; BMP4; BMP8 Gene; Biological; Biological Assay; Cell Differentiation process; Cell Lineage; Cells; Cellular biology; Characteristics; Chromosomes; Clinical; Communities; Complex; Core Facility; Couples; Data; Derivation procedure; Development; Diagnostic; ES Cell Line; Elements; Embryo; Endometrium; Event; Family; Family member; Female; Female infertility; Fertilization; Fetus; Frequencies; Gene Family; Genes; Genetic; Genetic Variation; Genetic screening method; Genome; Germ Cells; Growth; Health; Homologous Gene; Human; Human Biology; Human Development; Human Genetics; Human Genome; In Vitro; Infertility; Intracytoplasmic Sperm Injections; Invertebrates; Knowledge; Link; Maintenance; Meiosis; Menstrual cycle; Missense Mutation; Modeling; Molecular; Molecular Genetics; Molecular Profiling; Mus; Mutation; Names; Pathway interactions; Placentation; Population; Primates; Proteins; Publishing; Quality of life; Registries; Reporter; Reproduction; Reproductive Biology; Research; Research Personnel; Role; Science; Scientist; Structure; Structure of primordial sex cell; System; Testing; Time; Transcriptional Activation; Translations; Transplantation; UC01; UC06; United States National Institutes of Health; Variant; WA01 cell line; WA09 Cell Line; Woman; Y Chromosome; developmental genetics; egg; embryonic stem cell; family structure; fly; gene function; genetic manipulation; genetic variant; human embryonic stem cell; human embryonic stem cell line; implantation; in vivo; male; man; member; men; mutant; novel therapeutics; reproductive; response; sex; sex-specific imprints; sperm cell; success; tool; trophoblast

Infertility afflicts approximately 10-15% of couples and has causes linked to all the major events in the reproductive pathways, from development of functional eggs and sperm, to fertilization, embryonic transcriptional activation, implantation, placentation and growth of a viable fetus. In spite of the frequency of infertility and impact on the quality of life of those affected, little is known of underlying molecular and genetic causes. Nonethless, recent advances in assisted reproductive techniques, reproductive biology, human embryonic stem cell (hESC) biology and human genetics, may now allow us to overcome two historicallysignificant limitations in human reproductive studies: namely, the inaccessibility of early human development to biological exploration and the genetic-intractability of the human genome during development. In this proposal, we use the powerful tools of hESC biology and human genetics to test the hypotheses: 1) that multiple members of the DAZ (Deleted in AZoospermia) gene family are required for the formation and/or maintenance of nascent human germ cells and 2) that common genetic variants and unique mutations, enriched in chromosomes of infertile men and women, modulate early human germ cell development in both sexes. Our specific aims are: Aim 1. Define the baseline molecular, temporal and genetic characteristics of differentiation of hESCs and mESCs to the germ cell lineage in vitro and in.vivo. Aim 2. Silence human DAZ, and human and mouse DAZL and BOL genes and assess germ cell development. Aim 3. Examine functional significance of a common variant and a rare mutation in the DAZ gene family in the human population and relate results to human genetic studies and clinical findings. This research is particularly responsive to the health concerns of infertile couples who seek assisted reproductive technologies in hopes of achieving biological parenthood. Indeed, successful completion of the proposed research promises to strengthen our basic understanding of the remarkable pathways by which human germ cells develop, provide useful tools for basic scientists to study human germ cell development, and contribute to the development of novel therapeutics and validated diagnostic genetic tests for clinical use. The research would greatly benefit from the establishment of a center that provides interactions across the community and access to valuable core facilities. This research uses hESC lines from the NIH Registry (UC01, UC06, WA01 and WA09).

不孕症困扰着大约 10-15% 的夫妇，其原因与世界上所有重大事件有关。 生殖途径，从功能性卵子和精子的发育到受精、胚胎 转录激活、植入、胎盘和存活胎儿的生长。尽管出现的频率 不孕症及其对受影响者生活质量的影响，人们对潜在的分子和遗传知之甚少 原因。尽管如此，辅助生殖技术、生殖生物学、人类生殖技术的最新进展 胚胎干细胞（hESC）生物学和人类遗传学现在可能使我们能够克服两个具有历史意义的难题 人类生殖研究的局限性：即无法了解早期人类发展 生物探索和人类基因组在发育过程中的遗传难易性。在这个 根据建议，我们使用 hESC 生物学和人类遗传学的强大工具来检验假设：1） DAZ（在 AZoospermia 中缺失）基因家族的多个成员是形成和/或 维持新生人类生殖细胞，2) 常见的遗传变异和独特的突变， 富含不育男性和女性的染色体，调节早期人类生殖细胞发育 性别。我们的具体目标是： 目标 1. 定义基线分子、时间和遗传特征 hESC 和 mESC 在体外和体内分化为生殖细胞谱系。目标 2. 沉默人类 DAZ， 和人类和小鼠 DAZL 和 BOL 基因并评估生殖细胞发育。目标 3. 检查功能 DAZ 基因家族中常见变异和罕见突变在人群中的意义 将结果与人类遗传学研究和临床发现联系起来。这项研究特别响应 寻求辅助生殖技术以期实现生育目标的不孕夫妇的健康问题 亲生父母身份。事实上，成功完成拟议的研究有望加强我们的 对人类生殖细胞发育的显着途径的基本了解，提供有用的工具 供基础科学家研究人类生殖细胞的发育，并为新型药物的开发做出贡献 临床使用的治疗方法和经过验证的诊断基因测试。该研究将大大受益于 建立一个中心，提供跨社区的互动并获得宝贵的核心资源 设施。本研究使用 NIH 登记处的 hESC 系（UC01、UC06、WA01 和 WA09）。