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Oogonial Stem Cell Characterization in POI and NHP

POI 和 NHP 中的卵原干细胞表征

基本信息

批准号：
9150175
负责人：
Erin Wolff
金额：
$ 50.32万
依托单位：
EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
依托单位国家：
美国
项目类别：
财政年份：
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/9150175
关键词：
Adrenal Cortex Hormones Adult Age Aging Amenorrhea Antibodies Back Biological Preservation Bone Marrow Calculi Cell Line Cell Separation Cells Child Clinical Clinical Trials Control Groups Controlled Study Cross-Over Studies Danazol Disease Disease model Estradiol Failure Female Fertility Fertility Rates Future Generations Genetic Germ Cells Germ Lines Goals Gonadotropins Homologous Gene Hormonal Human Incidence Infertility Meiosis Menopause Menstrual cycle Mitotic Modeling Mus Nature Neonatal Oocytes Operative Surgical Procedures Ovarian Ovary Ovulation Induction Patients Pituitary Gland Placentation Play Population Pregnancy Premature Ovarian Failure Primates Production Protocols documentation Quality of life Radiation Randomized Controlled Trials Replacement Therapy Reporting Reproduction Reproductive Physiology Research Design Risk Rodent Sleep Stem Cell Research Stem cells Therapeutic Therapeutic Intervention Time Translating Transplantation Update Woman Wood material Xenograft Model adult stem cell age related bone health chemotherapy control trial egg exhaustion germline stem cells human disease magnetic beads nonhuman primate offspring peripheral blood postnatal precursor cell pregnant premature primary ovarian insufficiency prospective randomized placebo controlled trial reproductive systematic review young woman

项目摘要

Premature ovarian failure/Primary ovarian insufficiency occurs due to idiopathic causes or following chemotherapy or radiation, and results in the inability of a woman to have her own genetic offspring. Currently, donor eggs from younger women are the only option for these women, given a lack of pharmacologic or surgical treatments to restore ovarian function. Recently, several new stem cell advances have occurred which could be used in future strategies to treat women with premature ovarian aging. Until recently, it was thought that female ovarian germline stem cells (aka ovarian stem cells, oogonial stem cells, OSCs, egg precursor cells, or EggPCs) did not exist. However, these cells have now been isolated in both a murine and human models using magnetic beads and FACS with antibodies against the germ line marker Ddx4 (aka Mouse Vasa Homologue), cultured ex vivo with mitotic expansion, and transplanted in murine and human xenograft models. Adult OSCs were able to enter into meiosis after transplantation back into a donor ovary, where they gave rise to offspring in mice, raising the possibility of therapeutic potential. The goal of this project is to translate technical advances in stem cell research into ways to help women with reproductive disorders. The overall goal of lab is to rapidly translate these reproductive stem cell breakthroughs to clinical trials. However, significant differences in reproductive physiology exist between rodents and primates (e.g. menstrual cycles and hemachorial placentation), which make it critical to perform proof of concept studies in non human primate (NHP) to determine the viability of this approach for future human therapy. As the incidence of infertility rises and women continue to delay reproduction, more fertility preservation options are needed. If this OSC approach is established, all women could bank ovarian stem cells at young ages for later use. This approach would mitigate age related risks of delayed reproduction and provide fertility preservation for unforeseen future idiopathic or iatrogenic premature ovarian failure.

卵巢早衰/原发性卵巢功能不全是由于特发性原因或化疗或放疗后发生的，并导致女性无法拥有自己的遗传后代。目前，由于缺乏恢复卵巢功能的药物或手术治疗，来自年轻女性的捐赠卵子是这些女性的唯一选择。最近，出现了几种新的干细胞进展，可用于未来治疗卵巢早衰妇女的策略。直到最近，人们才认为女性卵巢生殖系干细胞（又名卵巢干细胞，卵原干细胞，OSCs，卵前体细胞或EggPC）不存在。然而，这些细胞现在已经在鼠和人模型中使用磁珠和具有针对生殖系标记物Ddx 4（aka Mouse Vasa Homologue）的抗体的FACS分离，离体培养并进行有丝分裂扩增，并移植到鼠和人异种移植模型中。成年OSCs在移植回供体卵巢后能够进入减数分裂，在那里它们在小鼠中产生后代，提高了治疗潜力的可能性。该项目的目标是将干细胞研究的技术进步转化为帮助患有生殖障碍的妇女的方法。实验室的总体目标是将这些生殖干细胞突破迅速转化为临床试验。然而，啮齿动物和灵长类动物之间存在生殖生理学的显著差异（例如月经周期和血绒毛膜胎盘形成），这使得在非人灵长类动物（NHP）中进行概念验证研究以确定这种方法用于未来人类治疗的可行性至关重要。随着不孕症发病率的上升和妇女继续推迟生育，需要更多的生育能力保留选择。如果这种OSC方法得以建立，所有女性都可以在年轻时储存卵巢干细胞供日后使用。这种方法将减轻与年龄相关的延迟生殖风险，并为不可预见的未来特发性或医源性卵巢早衰提供生育力保护。