Towards a preclinical model for overcoming infertility with induced pluripotent stem cells

建立利用诱导多能干细胞克服不孕症的临床前模型

• 批准号: 10630112
• 负责人: Amander Clark
• 金额: $ 59.76万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10630112
• 关键词: Adult; Affect; Age; Assisted Reproductive Technology; Basic Science; Cell Differentiation Induction; Cell Differentiation process; Cells; Characteristics; Collaborations; Couples; DNA Methylation; Development; Developmental Biology; Diagnosis; Disease; Embryo; Embryonic Development; Event; Female; Fertility; Future; Gametogenesis; Genomics; Germ Cells; Goals; Gonadal structure; Grant; Human; In Vitro; Individual; Infertility; Knowledge; Life; Life Cycle Stages; Link; Logic; Macaca; Macaca mulatta; Modeling; Molecular; Mus; Natural regeneration; Neonatal; Oocytes; Oogenesis; Oregon; Ovarian; Patients; Physiological; Population; Pre-Clinical Model; Primates; Reproduction; Research; Research Institute; Research Proposals; Rhesus; Signal Transduction; Skin; Somatic Cell; Structure of primordial sex cell; Technology; Testing; Testis; Translating; Transplantation; United States; Woman; Women' s Health; Work; Xenograft procedure; design; egg; fetal; human tissue; in vivo; induced pluripotent stem cell; induced pluripotent stem cell technology; infertility treatment; male; nonhuman primate; pregnant; prenatal; professor; reproductive; restoration; sex; sperm cell; stem cell differentiation; success

Summary Around 12% of women in the United States have problems getting pregnant and carrying a baby to term, with 7% of women and their partners being diagnosed as infertile. Some diagnoses of infertility can be overcome through Assisted Reproductive Technologies (ART), however these technologies require each partner to make functional gametes (eggs or sperm) for success. For those individuals incapable of making gametes, ART is not an option for overcoming a diagnosis of infertility. In this grant, we are developing a model for fertility restoration to the infertile patient using induced pluripotent stem cells (iPSCs). This basic research proposal is aimed at testing the hypothesis that prenatal and neonatal gonadal somatic cells are required to instruct male and female germline cell differentiation using non human primate (NHP) iPSCs. The proposal under consideration is based upon the scientific premise with mouse (m) models that male and female miPSCs differentiated into mouse primordial germ cell (PGC)-like cells (mPGCLCs) will undergo sex-specific differentiation when transplanted with prenatal gonadal somatic cells, or directly into neonatal niches. The success of this technology in the mouse was first built upon a fundamental understanding of mouse germline cell development, particularly during prenatal life. Here, we propose three aims in which we will use developmental biology, genomics and transplantation to understand the cell and molecular basis of sex- specific PGC differentiation in vivo using NHPs. This knowledge will be used to differentiate male and female NHP iPSCs towards PGCLCs that can undergo sex-specific differentiation using the signaling logic of the prenatal gonad, or alternatively following transplantation or culture with prenatal or neonatal gonadal somatic cells. At the conclusion of this proposal, we will have determined the extent to which NHP PGCLCs are capable of sex-specific differentiation within prenatal and neonatal gonadal niches. This work will be used to inform future studies aimed at recreating male and female gametogenesis from NHP's entirely in vitro.

总结 在美国，大约12%的女性在怀孕和分娩方面存在问题， 7%的女性及其伴侣被诊断为不育。一些不孕症的诊断可以克服 通过辅助生殖技术（ART），然而，这些技术要求每个合作伙伴， 功能性配子（卵子或精子）的成功。对于那些不能制造配子的人来说，ART是 不是克服不孕症诊断的一个选择。在这项资助中，我们正在开发一个生育模型， 使用诱导多能干细胞（iPSC）恢复不育患者。这项基础研究计划是 旨在验证产前和新生儿性腺体细胞需要指导男性生殖的假设， 和使用非人灵长类（NHP）iPSC的雌性生殖系细胞分化。中的提案 考虑是基于小鼠（m）模型的科学前提， 分化为小鼠原始生殖细胞（PGC）样细胞（mPGCLC）将经历性别特异性 当与产前性腺体细胞一起移植或直接移植到新生儿小生境中时，的 这项技术在小鼠中的成功首先建立在对小鼠生殖系的基本理解之上 细胞发育，特别是在产前。在这里，我们提出了三个目标，我们将使用 发育生物学，基因组学和移植，以了解性别的细胞和分子基础- 使用NHP的体内特异性PGC分化。这些知识将用于区分男性和女性 NHP iPSC向PGCLC转化，PGCLC可以使用NHP iPSC的信号逻辑进行性别特异性分化。 产前性腺，或者在移植或培养产前或新生儿性腺体细胞后 细胞在本提案结束时，我们将确定NHP PGCLC在多大程度上 能够在产前和新生儿性腺小生境中进行性别特异性分化。这项工作将用于 为将来的研究提供信息，这些研究旨在完全在体外从NHP中重建雄性和雌性配子发生。