Aging and Ovarian Stem Cell Niche Dysfunction

衰老与卵巢干细胞生态位功能障碍

基本信息

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
项目类别：
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

项目摘要

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涉及干细胞功能障碍在与衰老相关的器官功能退化中发挥核心作用的可能性。最近的研究表明，成年哺乳动物卵巢中存在卵原干细胞（OSC）。 OSC的存在提出了一种可能性，即卵巢衰老（以含有卵母细胞的卵泡的丧失和耗尽为标志）可能同样涉及干细胞功能的逐渐丧失。因此，现在确定 OSC 在卵巢功能和衰老中的生理作用非常重要。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基于干细胞的有机衰老机制。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。这些小鼠模型的独特之处在于，可以使用自杀基因技术选择性地靶向和消除分化的 OSC 子细胞。在我们的初步数据中，我们表明选择性破坏这些 OSC 分化途径会导致基因定义的可逆性原始卵泡损失。这些发现支持成年期哺乳动物卵巢中卵母细胞储备的维持涉及来自 OSC 的新卵母细胞的主动输入。这些数据也为未来研究卵巢生物学和疾病发病机制奠定了坚实的基础，具有前所未有的可能性，包括了解女性生殖衰老，从而解释 OSC 对卵巢功能的贡献。该提案的具体目标是：1）利用我们开发的新型 sg-Tg 小鼠，确定 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消融； 2）评估神经胶质细胞源性神经营养因子（GDNF）和成纤维细胞生长因子（FGF9）分别作为刺激OSC增殖和抑制OSC减数分裂分化的可能的OSC生态位因子； 3) 表征 OSC 有丝分裂活性增加期间的 OSC 生态位，并检查血管内皮细胞对生态位功能的参与； 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，以在体外重现 OSC-生态位相互作用，并检查衰老对 OSC 活性的影响。最终，这些信息可能会被用来开发新的、有针对性的治疗方法，通过在需要时刺激 OSC 活性来增加卵母细胞储备，从而挽救卵巢功能——例如卵巢早衰患者、高龄产妇（推迟年龄相关的卵巢功能衰竭和更年期）或女性癌症患者（在抗癌治疗后挽救她们的卵巢功能和生育能力）——所有这些情况都代表了日益增加的公共卫生相关性。