Developing human gonad organoids to promote germ cell differentiation

开发人类性腺类器官以促进生殖细胞分化

基本信息

批准号：
10475265
负责人：
Michael Buszczak
金额：
$ 20.5万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10475265
关键词：
Adopted Affect Animal Model Automobile Driving Back Benchmarking Biological Models Cell Differentiation process Cell Maturation Cell physiology Cells Coculture Techniques Complex DNA Double Strand Break DNA Repair Defect Derivation procedure Development Diagnosis Double Strand Break Repair Down Syndrome Elements Engineering Exhibits Experimental Models Fetal Development Fostering Gametogenesis Genetic Diseases Genome Germ Cells Goals Gonadal structure Human In Vitro Individual Infertility Intermediate Mesoderm Invaded Licensing Mammalian Cell Mammals Medical Meiosis Methods Mus Oogenesis Organoids Ovarian Ovarian aging Ovary Pathway interactions Planets Population Process Property Protocols documentation Rattus Reproduction Reproductive Biology Reproductive Sciences Science Selfish DNA Somatic Cell Standardization Structure of primordial sex cell Study models Supporting Cell Testing Totipotency Work age related cell type design egg evidence base experience experimental study fetal human female human fetal cells in vivo induced pluripotent stem cell induced pluripotent stem cell technology insight kidney cell novel novel therapeutics prevent reconstitution single cell sequencing sperm cell success

项目摘要

Summary Germ cells are essential for the propagation of our species. Disruption of normal germ cell differentiation and function can result in infertility and genetic disorders in the progeny of affected individuals. However, many of the mechanisms that govern the formation and function of germ cells remain poorly understood. Our long-term goal is to identify and characterize pathways that regulate germ cell specific processes. However, the study of human gametogenesis remains largely impractical because specific steps of the process remain experimentally inaccessible. In addition, there are key differences between human germ cells and those of other mammals including mice and rats, limiting the usefulness of animal models for studying and manipulating specific aspects of human gametogenesis. To overcome these obstacles, we propose to engineer a transformative and scalable in vitro platform for reconstituting human gametogenesis. Towards this goal, we seek to develop novel methods for driving human induced pluripotent stem (iPS) cells to differentiate into every cell type found within human female gonads. Based of evidence from experimental models, we anticipate mixing iPS cell-derived germ cells with the appropriate combination of iPS cell-derived somatic support cells will promote further steps in the process of gametogenesis. The successful completion of this proposal will revolutionize the study of human reproduction and provide a scalable platform for developing new therapies to treat infertility and prevent a broad range of genetic disorders.

概括生殖细胞对于我们物种的繁殖至关重要。破坏正常生殖细胞分化和功能可能导致后代不育和遗传疾病受影响的个人。然而，许多控制形成和生殖细胞的功能仍然知之甚少。我们的长期目标是确定并表征调节生殖细胞特定过程的途径。然而，研究人类配子发生在很大程度上仍然不切实际，因为该过程的具体步骤仍然是实验上无法访问的。此外，人类之间也存在重大差异。生殖细胞和其他哺乳动物（包括小鼠和大鼠）的生殖细胞，限制了其用途用于研究和操纵人类配子发生的特定方面的动物模型。为了克服这些障碍，我们建议设计一个变革性的、可扩展的重建人类配子发生的体外平台。为了这个目标，我们寻求开发驱动人类诱导多能干细胞（iPS）的新方法细胞分化成人类女性性腺中发现的每种细胞类型。基于根据实验模型的证据，我们预计混合 iPS 细胞衍生的生殖细胞与 iPS 细胞衍生的体细胞支持细胞的适当组合将促进配子发生过程中的进一步步骤。本次提案的顺利完成将彻底改变人类生殖研究，并提供一个可扩展的平台开发治疗不孕症和预防多种遗传性疾病的新疗法。