Mitochondrial Dynamics in Female Reproduction

女性生殖中的线粒体动力学

• 批准号: 10767376
• 负责人: Yuan Wang
• 金额: $ 15.65万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10767376
• 关键词: Acceleration; Administrative Supplement; Affect; Agonist; Apoptosis; Biology; Birth; Breeding; Cell Lineage; Cell Proliferation; Cell physiology; Couples; Defect; Development; Developmental Process; Drosophila genus; Ensure; Female; Fertility; Funding; Gender; Germ Cells; Goals; Human; Impairment; Infertility; Link; Mammals; Metabolic; Metabolism; Mitochondria; Mitochondrial DNA; Mus; Mutant Strains Mice; Mutate; National Institute of General Medical Sciences; Oocytes; Ovarian; Ovarian Follicle; Parents; Play; Process; Publishing; Regulation; Reproduction; Reproductive Medicine; Research; Role; Series; Somatic Cell; Spermatocytes; Spermatogenesis; Stimulus; Strategic Planning; Supporting Cell; Testing; United States National Institutes of Health; Women' s Health; conditional knockout; cost; cost efficient; experimental study; female fertility; germline stem cells; improved; individual response; insight; male; male fertility; mitochondrial DNA mutation; mitochondrial dysfunction; mitochondrial fitness; mouse model; mutant; novel; novel strategies; reproductive; sex; stem cell differentiation; stem cells

PROJECT SUMMARY Mitochondrial fitness is critical for their proper functions in diverse cellular and developmental processes. Strong evidence links mitochondrial dysfunction to reduced fertility in humans. However, the mechanism underlying these connections, and whether any potential treatments of such mitochondrial defects may remedy these infertile cases, remain unknown. Mitochondrial features, activities, and functions are tightly regulated via mitochondrial fusion (mitofusion) and fission, collectively known as mitochondrial dynamics. Accumulating evidence from somatic cells support that mitochondrial dynamics not only enable coordinated responses of individual mitochondria to developmental stimuli and metabolic needs, but also ensure mitochondrial fitness. In addition, increased mitochondrial dynamics reduce mutant mitochondria in Drosophila oocytes, strongly suggesting conserved roles of mitochondrial dynamics in regulating mitochondrial fitness in reproduction. In the parent R01 of this supplement study, we aim to unveil novel functional mechanisms of how spermatogonial stem cell differentiation and male germ cell mitochondrial fitness are regulated by properly balanced mitofusion and fission. We have generated a series of genetically modified mouse models to achieve this goal but will only need male mice. On the other hand, published studies suggest that mitochondrial dynamics conservatively regulate mammalian reproduction in both sexes but via sex-specific mechanisms. Each mature oocyte contains about 100,000 mitochondria, 500-fold more than male germ cells, suggesting that very high mitochondrial activities are needed to support female reproduction. Studies with conditional knockouts of either pro- fusion or fission factors in female germ cells indeed support that mitochondrial dynamics are dispensable for ovarian follicular reserve. This supplement study aims to unveil the role of mitochondria dynamics in female fertility and underlying mechanisms, scientifically complementary to the parent R01. We will cost-efficiently use female mutant mice from the same breeding process for the proposed experiments, operationally complementary to the parent R01. Using mitochondrial DNA mutator mice and novel mitofusion agonists, we will determine the functional impacts on female reproduction and mitochondrial fitness by augmented mitochondrial dynamics. Study findings will fundamentally advance research in both mitochondrial biology and reproductive medicine by revealing sex-based commonalities and differences in the mitochondrial regulation of mammalian reproduction. Our study will also inform a novel strategy to treat impaired female fertility due to mitochondrial dysfunction. Findings from this study will significantly advance reproductive research related to women’s health, answering the call of this specific “Administrative Supplement for Research on Sex and/or Gender Influences” and serving well the strategic goals of the “2019-2023 Trans-NIH Strategic Plan for Women’s Health Research”.

项目摘要 线粒体适应性对于它们在大型细胞和发育过程中的适当功能至关重要。 有力的证据将线粒体功能障碍与人类的生育能力降低联系起来。但是，机制 这些连接的基础，以及这种线粒体缺陷的任何潜在治疗是否可能 补救这些不育病，尚不清楚。线粒体特征，活动和功能紧密 通过线粒体融合（线粒体）和裂变调节，统称为线粒体 动力学。从体细胞中积累的证据支持线粒体动力学不仅 实现单个线粒体的协调反应，以发展刺激和代谢需求， 但也要确保线粒体健身。另外，线粒体动力学增加了突变体 果蝇卵母细胞中的线粒体，强烈建议线粒体动力学的保守作用 调节繁殖中的线粒体适应性。在这项补充研究的父母R01中，我们的目标是 揭示精子干细胞分化和雄性生殖的新型功能机制 细胞线粒体适应性受到适当平衡的丝定渗和裂变的调节。我们已经生成了 一系列普遍修改的鼠标模型可以实现此目标，但只需要雄性小鼠。在 另一方面，已发表的研究表明，线粒体动力学保守调节哺乳动物 两性的繁殖，但通过性别特定的机制。每个成熟的卵母细胞都包含 100,000线粒体，比男性生殖细胞多500倍，这表明线粒体很高 需要活动以支持女性繁殖。通过有条件敲除任一的研究的研究 雌性生殖细胞中的融合或裂变因子确实支持线粒体动力学是可分配的 用于卵巢卵泡储备。这项补充研究旨在揭示线粒体动力学的作用 在女性的生育力和基本机制中，对父母R01进行科学完善。我们将 成本效率地使用来自同一育种过程的女性突变小鼠进行拟议的实验， 在操作上互补与父级R01。使用线粒体DNA突变器小鼠和新颖 derofusion激动剂，我们将确定对女性繁殖和线粒体的功能影响 通过增强线粒体动力学的健身。研究结果将从根本上进步 线粒体生物学和生殖医学都通过揭示基于性别的共同点和 哺乳动物繁殖的线粒体调节的差异。我们的研究也将为一本小说提供信息 治疗因线粒体功能障碍而导致女性生育受损的策略。这项研究的发现将 显着提高与妇女健康有关的复制研究，回答了这种特定的呼吁 “有关性和/或性别影响研究的行政补充”，并很好地服务于该战略 “ 2019 - 2023年妇女健康研究战略计划”的目标。