Equipment purchase request for parent R01 - Mitochondrial dynamics in spermatogonial differentiation

母体 R01 的设备购买请求 - 精原细胞分化中的线粒体动力学

基本信息

批准号：
10795361
负责人：
Yuan Wang
金额：
$ 5.85万
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/10795361
关键词：
Acceleration Adult Affect Architecture Area Biology Cell physiology Cells Couples Data Development Developmental Process Equilibrium Event Fluorescence Germ Cells Goals Guanosine Triphosphate Phosphohydrolases Health Impairment In Vitro Infertility Knockout Mice Male Infertility Mammals Metabolic Metabolism Mitochondria Organelles Output Oxidative Phosphorylation Parents Pattern Play Process Reactive Oxygen Species Reproduction Reproductive Medicine Research Respiration Role Series Signal Transduction Somatic Cell Spermatogenesis Spermatogonia Testing Testis Transplantation Undifferentiated cell type conditional knockout equipment acquisition insight male male fertility mitochondrial DNA mutation mitochondrial dysfunction mitochondrial fitness mouse model novel novel strategies postnatal real time monitoring sperm cell sperm quality stem cell differentiation stem cell self renewal stem cells

项目摘要

PROJECT SUMMARY Mitochondria are increasingly recognized as key players in a wide range of cellular and developmental processes, such as cell signaling, stem cell self-renewal, and lineage commitment, beyond their canonical roles in metabolism and oxidative phosphorylation. Such functional diversity is largely determined by the cell type- specific mitochondrial features, including mitochondrial number, architecture, distribution, and interaction with other subcellular organelles. These mitochondrial features are tightly regulated via mitochondrial fusion and fission, collectively known as mitochondrial dynamics, the alteration of which will lead to changing mitochondrial functions and activities in a cell type-specific manner, and thus impacts cell fate decision, particularly during development and in stem cell differentiation. We found that upregulated mitochondrial respiration accompanied by increased reactive oxygen species (ROS) is required for postnatal spermatogonial stem cell differentiation. However, such elevated ROS can increase mitochondrial DNA mutations that are deleterious to mitochondrial fitness and cell functions. It remains elusive how stem cells properly balance mitochondrial activities to meet the competing need for increased mitochondrial respiration during differentiation while maintaining mitochondrial fitness. Our pilot data suggest that mitochondria fusion and fission are both upregulated in spermatogonial differentiation, which is essential for sustaining proper male fertility. We thus propose to reveal a novel functional mechanism of how spermatogonial differentiation and germ cell mitochondrial fitness are regulated by concurrently accelerated and properly balanced mitochondrial fusion and fission. To achieve this goal, we will integrate a series of genetically modified mouse models with in vitro spermatogonial differentiation and transplantation approaches. Study findings will fundamentally advance research in both reproductive medicine and mitochondrial biology by explaining how spermatogonial differentiation is regulated via stage-specific mitofusion and fission, thereby unlocking a new area of discovery, namely, how mitochondrial function and health are maintained so in order to support critical and unique events of mammalian development. In addition, by revealing the impacts of mitochondrial dynamics on germ cell mitochondrial fitness, this project will critically inform a novel strategy to treat impaired male fertility due to mitochondrial dysfunctions.

项目概要线粒体越来越被认为是广泛的细胞和发育过程中的关键参与者，例如细胞信号传导、干细胞自我更新和谱系承诺，超出了它们在代谢和氧化磷酸化。这种功能多样性很大程度上取决于细胞类型特定的线粒体特征，包括线粒体数量、结构、分布以及与线粒体的相互作用其他亚细胞器。这些线粒体特征通过线粒体融合受到严格调节裂变，统称为线粒体动力学，其改变将导致线粒体发生变化以细胞类型特异性的方式发挥功能和活动，从而影响细胞的命运决定，特别是在发育和干细胞分化。我们发现线粒体呼吸上调伴随着出生后精原干细胞分化所需的活性氧（ROS）增加。然而，这种升高的 ROS 会增加对线粒体有害的线粒体 DNA 突变。健身和细胞功能。干细胞如何正确平衡线粒体活动以满足分化过程中增加线粒体呼吸的竞争需求，同时维持线粒体健康。我们的试验数据表明，精原细胞中线粒体融合和裂变均上调分化，这对于维持适当的男性生育能力至关重要。因此，我们建议揭示一种新颖的功能精原细胞分化和生殖细胞线粒体适应性如何调节的机制同时加速和适当平衡线粒体融合和裂变。为了实现这一目标，我们将将一系列转基因小鼠模型与体外精原细胞分化相结合移植方法。研究结果将从根本上推进生殖医学的研究和线粒体生物学，解释精原细胞分化如何通过阶段特异性进行调节线粒体融合和裂变，从而开启了一个新的发现领域，即线粒体功能和健康如何保持这种状态是为了支持哺乳动物发育的关键和独特事件。此外，通过该项目揭示了线粒体动力学对生殖细胞线粒体健康的影响，为治疗因线粒体功能障碍而导致的男性生育能力受损提供了一种新策略。