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

摘要 随着细胞的老化，核孔恶化，导致核质运输失调。新兴 有证据表明，这种恶化是与衰老相关的衰退的致病因素。因此，以核孔为目标 复合体(NPC)，30个蛋白质，百万吨，异多聚体之间的唯一门户核和 细胞质，可能在促进健康衰老方面具有治疗价值。我们之前已经表明，NPC 通常情况下，二甲双胍是双胍类药物中的一种，可以阻止甚至逆转其恶化。 治疗2型糖尿病的处方。我们之前的工作发现了一条连接二甲双胍作用的保守途径 对线虫核质运输的调节和生长衰老的调节。 这一途径的中心特征是正常的线粒体功能促进了特定方面的运输 通过全国人大。随着生物体的老化，线粒体促进了核泄漏，使货物能够进出 细胞核不适当，导致与衰老相关的细胞功能下降。或者，当单元格 暴露于二甲双胍，一种线粒体复合体I能量学的调节剂，被动核运输 抑制会导致细胞生长停止并延长寿命。为了充分了解二甲双胍是如何执行其 在衰老过程中对细胞的影响，重要的是要确定其对核质运输的影响。我的假设 是双胍通过改变特定货物的被动和/或促进运输来延长寿命 全国人大。我将阐明核质运输动力学变化的作用机制 治疗衰老和延年益寿，以回应二甲双胍。我这个项目的目标是从两个方面全面 定义二甲双胍改变的核转运机制，以及2)鉴定和功能表征 核运输货物在老化过程中异常局部化，并通过二甲双胍恢复。作为一个无法解决的问题 与从事这项工作相关的后果，我将在老龄化方面获得最先进的方法论方面的关键培训 研究，使我能够在未来在衰老的基础生物学方面进行具有重大影响的工作。我的培训计划 在老龄化研究领域的领先机构和实验室担任导师使我能够很好地实现这些目标 目标。最终，鉴定异常定位的鼻咽癌货物在衰老中的作用，并表征它们在 衰老和二甲双胍介导的延长寿命有望照亮衰老和癌症的新治疗靶点 与衰老相关的疾病。

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.