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

基本信息

批准号：
10411980
负责人：
Amander Clark
金额：
$ 59.98万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10411980
关键词：
Adult Affect Age Assisted Reproductive Technology Basic Science 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 Libido 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&apos s Health Work base 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

项目摘要

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.

概括大约 12% 的美国女性在怀孕和生孩子方面存在问题，其中 7% 的女性及其伴侣被诊断为不孕症。一些不孕不育的诊断是可以克服的通过辅助生殖技术（ART），但是这些技术要求每个合作伙伴成功的功能性配子（卵子或精子）。对于那些无法产生配子的个体来说，ART 是不是克服不孕症诊断的选择。在这笔赠款中，我们正在开发一个生育模型使用诱导多能干细胞（iPSC）使不孕患者恢复健康。这项基础研究计划是旨在检验产前和新生儿性腺体细胞需要指导男性的假设以及使用非人灵长类 (NHP) iPSC 进行雌性生殖细胞分化。该提案根据考虑基于小鼠 (m) 模型的科学前提，即雄性和雌性 miPSC 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移植产前性腺体细胞或直接移植到新生儿微环境中时，可分化。这这项技术在小鼠身上的成功首先建立在对小鼠种系的基本了解之上细胞发育，特别是在胎儿期。在这里，我们提出了三个目标，我们将在其中使用发育生物学、基因组学和移植，以了解性别的细胞和分子基础使用 NHP 在体内进行特异性 PGC 分化。这些知识将用于区分男性和女性 NHP iPSC 向 PGCLC 发展，可以使用以下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 的程度能够在产前和新生儿性腺生态位内进行性别特异性分化。这项工作将用于为未来旨在完全在体外利用 NHP 重建雄性和雌性配子发生的研究提供信息。