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

项目总结