Mitochondrial Dynamics in Female Reproduction

女性生殖中的线粒体动力学

基本信息

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
项目类别：
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&apos 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

项目摘要

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”.

项目概要线粒体适应性对于其在不同细胞和发育过程中的正常功能至关重要。强有力的证据表明线粒体功能障碍与人类生育能力下降有关。这些联系的基础，以及这种线粒体缺陷的任何潜在治疗方法是否可以治疗这些不孕症的方法，线粒体的特征、活动和功能仍然未知。通过线粒体融合（有丝分裂）和裂变（统称为线粒体）进行调节来自体细胞的越来越多的证据支持线粒体动力学不仅。使个体线粒体能够对发育刺激和代谢需求做出协调反应，还可以确保线粒体的健康，此外，线粒体动力学的增加可以减少突变。果蝇卵母细胞中的线粒体，表明线粒体动力学的作用非常保守在本补充研究的母体 R01 中，我们的目标是调节生殖中的线粒体适应性。揭示精原干细胞分化和雄性生殖的新功能机制细胞线粒体的适应性是通过适当平衡的有丝分裂融合和裂变来调节的。一系列转基因小鼠模型可以实现这一目标，但只需要雄性小鼠。另一方面，已发表的研究表明线粒体动力学保守地调节哺乳动物两性生殖，但通过性别特异性机制每个成熟卵母细胞含有约 100,000 个线粒体，比男性生殖细胞多 500 倍，表明线粒体数量非常高需要开展活动来支持女性生殖。女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有可无的这项补充研究旨在揭示线粒体动力学的作用。在女性生育力和潜在机制方面，我们将与母体 R01 进行科学补充。经济高效地使用来自同一育种过程的雌性突变小鼠进行拟议的实验，使用线粒体 DNA 突变小鼠，在操作上与亲代 R01 互补。线粒体融合激动剂，我们将确定对女性生殖和线粒体的功能影响通过增强线粒体动力学来增强健康的研究结果将从根本上推进相关研究。通过揭示基于性别的共性和线粒体生物学和生殖医学我们的研究还将揭示哺乳动物生殖线粒体调节的差异。这项研究的结果将提出治疗因线粒体功能障碍而导致的女性生育能力受损的策略。响应这一特定号召，显着推进与妇女健康相关的生殖研究《性别和/或性别影响研究行政补充》并服务于战略 “2019-2023 年跨 NIH 女性健康研究战略计划”的目标。