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: 7633409
• 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
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7633409
• 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).

大约10-15%的夫妇患有不孕症，其原因与世界上所有主要事件有关