The Role of Nuclear Transport Dynamics in Metformin's Geroprotective Effects

核转运动力学在二甲双胍的老年保护作用中的作用

• 批准号: 10407953
• 负责人: Talia Hart
• 金额: $ 4.97万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10407953
• 关键词: Age; Aging; Biguanides; Biology; Biology of Aging; Caenorhabditis elegans; Carrier Proteins; Cell Aging; Cell Nucleus; Cell physiology; Cells; Complex; Cytoplasm; Deterioration; Disease; Dose; Drug usage; Exclusion; Exposure to; FRAP1 gene; Future; Genetic; Geroscience; Goals; Growth; Health; Human; Institution; Invertebrates; Laboratories; Link; Longevity; Malignant Neoplasms; Mediating; Mentorship; Metformin; Methodology; Microscopy; Mitochondria; Modeling; Molecular Genetics; Monomeric GTP-Binding Proteins; Nematoda; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Nuclear Localization Signal; Nuclear Pore; Nuclear Pore Complex; Organism; Pathogenicity; Pathway interactions; Permeability; Pharmaceutical Preparations; Phase; Phenotype; Phosphotransferases; Play; Positioning Attribute; Process; Proteins; Proteomics; Quantitative Microscopy; Regulation; Research; Role; Therapeutic; Time; Training; Translating; Travel; Visualization; Work; World Health Organization; career; cell age; cell growth; combat; drug repurposing; epidemiologic data; functional genomics; healthspan; healthy aging; in silico; insight; interest; loss of function; member; new therapeutic target; novel; nucleocytoplasmic transport; response; therapy development; trafficking

Abstract As the cell ages, the nuclear pore deteriorates, leading to dysregulated nucleocytoplasmic transport. Emerging evidence indicates that this deterioration is pathogenic in aging-related decline. Thus, targeting the nuclear pore complex (NPC), the 30+ protein, megadalton, heteromultimeric sole gateway between the nucleus and the cytoplasm, may be of therapeutic value in promoting healthy aging. We have previously shown that NPC deterioration can be halted or even reversed by metformin, a member of the biguanide class of drugs commonly prescribed in type 2 diabetes. Our previous work identified a conserved pathway that connects metformin action to the regulation of nucleocytoplasmic transport and modulation of growth and aging in the nematode, C. elegans. The central feature of this pathway is that normal mitochondrial function facilitates specific aspects of transport through the NPC. As organisms age, mitochondria facilitate nuclear leakiness, allowing cargoes to exit and enter the nucleus inappropriately, contributing to aging-related declines in cellular function. Alternatively, when cells are exposed to metformin, a modulator of mitochondrial complex I energetics, passive nuclear transport is inhibited leading to halted cell growth and increased lifespan. To fully understand how metformin exacts its effects on the cell in aging, it is important to determine its impact on nucleocytoplasmic trafficking. My hypothesis is that biguanides promote longevity by altering passive and/or facilitated transport of specific cargoes through the NPC. I will elucidate the functional mechanisms by which changes in nucleocytoplasmic transport dynamics govern aging and longevity in response to metformin. The goal of my project is twofold 1) to comprehensively define mechanisms of altered nuclear transport with metformin, and 2) to identify and functionally characterize nuclear transport cargoes that are aberrantly localized in aging and restored by metformin. As an inextricably linked consequence of conducting this work, I will obtain critical training in state-of-the-art methodologies in aging research, enabling me to do future high impact work on the fundamental biology of aging. My plan for training and mentorship at leading institutions and laboratories in aging research positions me well to achieve these goals. Ultimately, identification of aberrantly localized NPC cargoes in aging, and characterization of their role in aging and metformin-mediated lifespan extension is expected to illuminate new therapeutic targets in aging and aging-related disease.

摘要 随着细胞老化，核孔退化，导致核质转运失调。新兴 有证据表明，这种恶化在与衰老有关的衰退中是致病的。因此，靶向核孔 复合物（NPC），30+蛋白质，兆道尔顿，细胞核和细胞核之间的异源多聚体唯一通道。 细胞质，可能具有促进健康衰老的治疗价值。我们之前已经证明，NPC 二甲双胍可以阻止甚至逆转恶化，二甲双胍是双胍类药物的一种， 2型糖尿病的治疗方法我们以前的工作确定了一个保守的途径，连接二甲双胍的行动 对线虫的核质运输和生长衰老的调节，C.优美的 这一途径的中心特征是正常的线粒体功能促进特定方面的运输 通过NPC。随着有机体的衰老，线粒体促进核泄漏，允许货物进出 不适当的细胞核，导致衰老相关的细胞功能下降。或者，当细胞 暴露于二甲双胍，一种线粒体复合物I能量学的调节剂，被动核转运是 抑制导致停止细胞生长和增加寿命。为了充分了解二甲双胍是如何 在衰老中对细胞的影响，重要的是确定其对核质运输的影响。我的假设 双胍通过改变特定货物的被动和/或便利运输， NPC。我将阐明核质转运动力学变化的功能机制 控制衰老和长寿。我的项目的目标是双重的1）全面 确定二甲双胍改变核转运的机制，和2）识别和功能表征 核转运货物在老化中异常定位并通过二甲双胍恢复。作为一个不可分割的 进行这项工作的相关后果，我将获得国家的最先进的老化方法的关键培训 研究，使我能够在未来对衰老的基础生物学进行高影响力的工作。我的训练计划 在老龄化研究的领先机构和实验室的指导，使我能够很好地实现这些目标。 目标.最终，识别老化中异常定位的NPC货物，并表征它们在老化中的作用。 衰老和二甲双胍介导的寿命延长有望阐明衰老的新治疗靶点， 与衰老有关的疾病。