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: 8316123
• 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/8316123
• 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; 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.

描述（由申请人提供）：干细胞生物学最令人兴奋的领域之一与干细胞功能障碍在器官功能的衰老相关恶化中起着核心作用的可能性。最近的研究表明，成年哺乳动物卵巢中存在卵巢（卵母细胞生产）干细胞（OSC）。 OSC的存在增加了以下可能性，即以含卵母细胞的卵泡损失和精疲力尽的卵巢衰老可能同样涉及干细胞功能的逐渐丧失。因此，现在重要的是建立OSC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，从而将OSC作为模型来洞悉基于干细胞的生物衰老机制。具体而言，我建议使用过去三年来开发的新型自杀基因转基因（SG-TG）小鼠模型来研究这一点。这些小鼠模型是独一无二的，因为可以使用自杀基因技术选择性地靶向和消融。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会导致原始卵泡的遗传定义可逆损失。这些发现支持成年期间哺乳动物卵巢中卵母细胞储备的维持涉及来自OSC的新卵母细胞的积极输入。这些数据还为对卵巢生物学和疾病发病机理的未来研究奠定了坚实的基础，并具有前所未有的可能性，包括对女性生殖衰老的理解，这些衰老构成了OSC对卵巢功能的贡献。该提案的具体目的是：1）使用我们开发的新型SG-TG小鼠在卵巢衰老中建立OSC的生理作用，其中可以选择性地消融osc子女细胞； 2）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）分别在刺激OSC增殖和抑制OSC减数分裂分化方面作为可能的OSC细分因子； 3）表征OSC选择率在增加的OSC有丝分裂活性的时期，并检查血管内皮细胞参与小裂功能；和4）通过使用卵巢体细胞作为进料细胞来概括OSC-NICHE相互作用，并检查衰老对OSC活性的影响，从而发展了改善的OSC培养条件。最终，这些信息可用于开发新颖和有针对性的治疗剂，通过增加卵母细胞储备来通过刺激OSC活动来挽救卵巢功能，例如，在卵巢过早衰竭的患者中，在母亲年龄的女性中，在卵巢过早的患者中（在母亲年龄较高的卵巢衰竭和卵巢癌症患者）中（以挽救他们的卵巢癌和卵子的能力），以挽救卵子的能力，以挽救他们的能力，以使其能够养成卵子的能力，以使其能够屈服于卵子，以使其能够屈服于卵子的养育功能）提高公共卫生相关性。