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: 8190097
• 负责人: Ning Wang
• 金额: $ 9.05万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-15 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8190097
• 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; Stem cells; 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; public health relevance; regenerative; reproductive; stem cell biology; stem cell differentiation; stem cell niche; suicide gene; therapeutic target; transgenic suicide gene

DESCRIPTION (provided by applicant): 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 public health relevance. PUBLIC HEALTH RELEVANCE: Ovarian aging is an inevitable process that affects every woman. Maintenance of ovarian function in aging females might provide a means to achieve significant improvements in health, well-being and life expectancy. Thus, with efforts to continue to extend life span, the question of how to delay or even reverse the deleterious effect of ovarian aging has gained increasing public health relevance.

描述（由申请人提供）：干细胞生物学最令人兴奋的领域之一涉及干细胞功能障碍在与衰老相关的器官功能恶化中起核心作用的可能性。最近的研究表明，卵原干细胞（OSCs）存在于成年哺乳动物的卵巢中. OSCs的存在增加了卵巢衰老的可能性，卵巢衰老的标志是含卵母细胞的卵泡的丢失和耗尽，可能同样涉及干细胞功能的进行性丧失。因此，现在重要的是要建立卵巢干细胞在卵巢功能和衰老中的生理作用。我的长期目标是确定衰老过程如何对OSC功能产生负面影响，从而使用OSC作为模型来深入了解生物体衰老的干细胞机制。具体来说，我建议使用我们在过去三年中开发的新型自杀基因转基因（sg-Tg）小鼠模型来研究这一点。这些小鼠模型是独特的，因为分化的OSC子细胞可以使用自杀基因技术选择性靶向和消融。在我们的初步数据中，我们表明，这些OSC分化途径的选择性破坏导致遗传定义的原始卵泡的可逆损失。这些研究结果支持了成年期哺乳动物卵巢中卵母细胞储备的维持涉及来自OSCs的新卵母细胞的主动输入。这些数据也为卵巢生物学和疾病发病机制的未来研究奠定了坚实的基础，具有前所未有的可能性，包括理解女性生殖衰老，解释OSC对卵巢功能的贡献。本研究的具体目的是：1）利用我们开发的新型sg-Tg小鼠建立OSC在卵巢衰老中的生理作用，其中分化的OSC子细胞可以被选择性地消融; 2）评估胶质细胞源性神经营养因子（GDNF）和成纤维细胞生长因子（FGF 9）作为可能的OSC生态位因子，分别刺激OSC增殖和抑制OSC减数分裂分化; 3）表征在OSC有丝分裂活性增加的时期期间的OSC小生境，并检查血管内皮细胞在小生境功能中的参与;以及，4）通过使用卵巢体细胞作为饲养细胞来开发改进的OSC培养条件，以离体重现OSC-小生境相互作用，并检查老化对OSC活性的影响。最终，这些信息可能会被用于开发新的和有针对性的治疗方法，通过刺激OSC活性增加卵母细胞储备来挽救卵巢功能，例如在卵巢早衰患者中，高龄产妇（推迟与年龄相关的卵巢衰竭和绝经）或女性癌症患者（在抗癌治疗后挽救卵巢功能和生育能力）-所有这些疾病都代表着越来越多的公共卫生相关性。 公共卫生相关性：卵巢衰老是一个不可避免的过程，影响着每个女性。维持老龄女性的卵巢功能可能会提供一种手段，以实现显着改善健康，福祉和预期寿命。因此，随着人们继续努力延长寿命，如何延缓甚至逆转卵巢衰老的有害影响的问题已经越来越多地与公共卫生相关。