Aging and Ovarian Stem Cell Niche Dysfunction

衰老与卵巢干细胞生态位功能障碍

• 批准号: 8732113
• 负责人: Ning Wang
• 金额: $ 24.88万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-30 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8732113
• 关键词: Ablation; Accounting; Adult; Affect; Age; Aging; Aging-Related Process; Area; Atrophic; Award; Biology; Biology of Aging; Birth; Cancer Patient; Cardiovascular system; Cell Culture Techniques; Cell Proliferation; Cell physiology; Cells; Clinical Medicine; Commit; Data; Deterioration; Disease; Elderly; Event; Failure; Female; Fertility; Fibroblast Growth Factor; Foundations; Functional disorder; Future; Goals; Health; Hematopoietic; In Vitro; Lead; Life Expectancy; Longevity; Maintenance; Mammals; Meiosis; Menopause; Mentors; Mitotic Activity; Modeling; Mus; Natural regeneration; Neuraxis; Neuroglia; Oocytes; Organ; Ovarian; Ovary; Pathogenesis; Pathway interactions; Patients; Personal Satisfaction; Phase; Phenotype; Physiological; Play; Premature Ovarian Failure; Primordial Follicle; Process; Proliferating; Property; Regulation; Reporter; Reporting; Role; Solid; Somatic Cell; Technology; Telomerase; Testing; Therapeutic; Tissues; Transgenic Mice; Transplantation; Undifferentiated; Vascular Endothelial Cell; Woman; adult stem cell; advanced maternal age; age related; aged; base; cancer therapy; daughter cell; embryonic stem cell; emerging adult; exhaustion; fibroblast growth factor 9; functional decline; improved; in vivo; induced pluripotent stem cell; insight; male; mouse model; neurotrophic factor; new therapeutic target; novel; offspring; ovarian failure; public health relevance; regenerative; reproductive; stem cell biology; stem cell differentiation; stem cell niche; stem cells; suicide gene; therapeutic target; transgenic suicide gene

Project Summary One of the most exciting areas of stem cell biology relates to the possibility that stem cell dysfunction plays central role in aging-related deterioration of organ function. Recent studies suggest that oogonial (oocyte- producing) stem cells (OSCs) exist in the adult mammalian ovary. Existence of OSCs raises the possibility that ovarian aging, marked by loss and exhaustion of oocyte-containing follicles, may similarly involve a progressive loss of stem cell function. Thus, it is now important to establish the physiological roles of OSCs in ovarian function and aging. My long-term goal is to determine how the aging process negatively affects OSC function, and thus use OSCs as a model to provide insight into stem cell-based mechanisms for organismal aging. Specifically, I propose to use novel suicide gene transgenic (sg-Tg) mouse models we have developed over the past three years to study this. These mouse models are unique in that differentiating OSC daughter cells can be selectively targeted and ablated using suicide gene technology. In our preliminary data, we show that selective disruption of these OSC differentiation pathways results in a genetically defined reversible loss of primordial follicles. These findings support that the maintenance of the oocyte reserve in mammalian ovaries during adulthood involves active input of new oocytes from OSCs. These data also lay a solid foundation for future studies of ovarian biology and disease pathogenesis with unprecedented possibilities, including an understanding of female reproductive aging that accounts for OSC contribution to ovarian function. The specific aims of this proposal are to: 1) establish the physiological roles of OSCs in ovarian aging using novel sg-Tg mice we have developed, in which differentiating OSC daughter cells can be selectively ablated; 2) evaluate glial cell-derived neurotrophic factor (GDNF) and fibroblast growth factor (FGF9) as possible OSC niche factors in stimulating OSC proliferation and suppressing OSC meiotic differentiation, respectively; 3) characterize OSC niches during periods of increased OSC mitotic activity and examine the participation of vascular endothelial cells in niche function; and, 4) develop improved OSC culture conditions by using ovarian somatic cells as feeder cells to recapitulate OSC-niche interaction ex vivo and examine the impact of aging on OSC activity. Ultimately, this information might be used to develop novel and targeted therapeutics that rescue ovarian function through increasing the oocyte reserve by stimulating OSC activity when it would be desirable - such as in patients with premature ovarian failure, in women of advanced maternal age (to postpone age- related ovarian failure and menopause) or in female cancer patients (to rescue their ovarian function and fertility after anti-cancer treatments) - all of these conditions represent increasing

项目摘要 干细胞生物学最令人兴奋的领域之一与干细胞功能障碍发挥的可能性有关 器官功能与衰老相关的恶化中的中心作用。最近的研究表明卵母细胞 - 成年哺乳动物卵巢中存在）干细胞（OSC）。 OSC的存在增加了这样的可能性 卵巢衰老以含卵母细胞卵泡的损失和疲惫为特征，可能涉及 干细胞功能的进行性丧失。因此，现在重要的是建立OSC的生理作用 卵巢功能和衰老。我的长期目标是确定衰老过程如何对OSC产生负面影响 功能，因此使用OSC作为模型，以洞悉基于干细胞的机制 老化。具体而言，我建议使用我们开发的新型自杀基因转基因（SG-TG）模型 在过去的三年中，研究了这一点。这些鼠标模型是独一无二的 使用自杀基因技术可以选择性地靶向和消融细胞。在我们的初步数据中，我们显示 这些OSC分化途径的选择性破坏导致遗传定义的可逆损失 原始卵泡。这些发现支持哺乳动物卵巢的卵母细胞储备的维护 在成年期间，涉及来自OSC的新卵母细胞的积极输入。这些数据也为 对卵巢生物学和疾病发病机理的未来研究具有前所未有的可能性，包括 了解女性生殖衰老，这是对卵巢功能的贡献。这 该提议的具体目的是：1）使用新颖的 我们已经开发的SG-TG小鼠，其中可以选择性地消融的OSC子女细胞。 2） 作为可能的OSC，评估神经胶质细胞衍生的神经营养因子（GDNF）和成纤维细胞生长因子（FGF9） 利基因素分别刺激OSC增殖和抑制OSC减数分裂分化； 3） 在OSC有丝分裂活性增加的期间，表征OSC细分市场并检查 利基功能中的血管内皮细胞； 4）通过使用卵巢发展改善的OSC培养条件 体细胞作为馈线细胞，以概括OSC-NIHICHE相互作用，并检查衰老对 OSC活动。最终，这些信息可能用于开发营救新颖和有针对性的治疗剂 通过刺激OSC活性来增加卵母细胞储备，卵巢功能是可取的 - 例如，在卵巢过早衰竭的患者中，在母亲年龄的女性中（推迟年龄 - 相关的卵巢衰竭和更年期）或女性癌症患者（营救其卵巢功能和 抗癌后的生育能力） - 所有这些疾病都代表着增加