The Role of Actin in Cellular Aging

肌动蛋白在细胞衰老中的作用

• 批准号: 9904302
• 负责人: Liza A Pon
• 金额: $ 46.21万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-15 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9904302
• 关键词: Actins; Affect; Age; Aging; Antigen-Presenting Cells; Biological Models; Caenorhabditis elegans; Cell Aging; Cell Maintenance; Cell Polarity; Cell Size; Cell division; Cell physiology; Cell surface; Cells; Cues; Cytokinesis; Cytoskeleton; Data; Defect; Eukaryota; Event; Excision; Family; Filopodia; Fingers; Foundations; Genes; Genetic Screening; Goals; Growth; Guanine Nucleotide Exchange Factors; Home environment; Immune response; Immune system; Inherited; Injury; Intervention; Laboratories; Link; Liver; Longevity; Lymphoid Tissue; Maintenance; Mammalian Cell; Mediating; Membrane Potentials; Mesenchymal Stem Cells; Microfilaments; Mitochondria; Modeling; Mothers; Movement; Muscle; Muscle Contraction; Myocardium; Myosin ATPase; Natural regeneration; Nature; Neck; Open Reading Frames; Organ; Organelles; Phase; Post-Translational Modification Site; Post-Translational Protein Processing; Process; Proteins; Reactive Oxygen Species; Regulation; Role; Saccharomycetales; Shapes; Signal Transduction; Sirtuins; Site; Skeletal Muscle; Skin; Structure; Swimming; System; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Testing; Time; Tissues; Work; Yeasts; aged; bone; cell cortex; cell motility; daughter cell; design; functional decline; healthspan; immunological synapse; member; normal aging; novel; oxidative damage; polarized cell; polymerization; prevent; public health relevance; recruit; response; rho; scaffold; sensor; wound healing; yeast genetics

 DESCRIPTION (provided by applicant): The actin cytoskeleton has essential roles in cellular functions including intracellular and cellular movement, establishment and maintenance of cell polarity, junctions and shape, muscle contraction, cell signaling and cytokinesis. While it is clea that actin function undergoes an age-associated decline in all systems studied including skeletal and cardiac muscle and the immune system, remarkably little is known about the role of the cytoskeleton in the normal aging process. Indeed, it is not clear whether modulation of the actin cytoskeleton can extend lifespan in mammalian cells. We obtained the first evidence that modulation of the actin cytoskeleton can extend lifespan using yeast as a model system. Previous studies from our laboratory revealed a role for the actin cytoskeleton in control of mitochondrial movement and promoting inheritance of fitter mitochondria by yeast daughter cells, and uncovered the mechanism underlying that process. Equally important, we found that promoting actin dynamics and function extends yeast lifespan and healthspan by a mitochondria-dependent mechanism. Finally, we obtained evidence that the actin cytoskeleton undergoes a decline in structure, polarization and function in yeast as they age, and that the defects in actin observed in old cells are similar to those observed upon deletion of Sir2p, the founding member of the Sirtuin family of lifespan regulators. In the R21 phase, we will study the mechanisms underlying age-linked declines in function of the actin cytoskeleton using yeast as a model system. Specifically, we will test whether there are age-linked declines in the stability o assembly of the actin cytoskeleton, and whether similar changes are observed in yeast in which lifespan has been extended or reduced by modulation of Sir2p. We obtained evidence that actin undergoes age-linked post- translational modifications (PTMs), and will determine the nature of those PTMs and the sites on actin where they occur. Finally, we will test whether the age-associated decline in actin polarization is due to defects in the polarization or activity of Cdc42 (a conserved Rho protein and actin regulator) and/or formins (which mediate actin polymerization and assembly at sites of polarized cell surface growth and are recruited to those sites by Cdc42). In the R33 phase, we will determine whether interventions that promote the structure, polarization and function of the actin cytoskeleton or prevent age-linked PTM of actin protein extend lifespan and/or healthspan. Moreover, we identified genes, including previously uncharacterized open reading frames, which enhance actin structure and polarity in a yeast genetic screen. We will test whether modulation of these genes and other actin-associated proteins can extend lifespan (R21 phase), and the mechanism underlying actin regulation by lifespan-extending genes (R33 phase). Since declines in actin function occur in aging mammalian cells, tissues and organs, and stabilizing actin extends lifespan in C. elegans, these studies will provide a foundation for understanding age-associated declines in the actin cytoskeleton, and may reveal interventions to promote actin function in lifespan and healthspan control in yeast and other eukaryotes.

 描述(申请人提供)：肌动蛋白细胞骨架在细胞功能中具有重要作用，包括细胞内和细胞运动、细胞极性的建立和维持、连接和形状、肌肉收缩、细胞信号和胞质分裂。尽管在所有被研究的系统中，包括骨骼肌、心肌和免疫系统在内的肌动蛋白功能都会随着年龄的增长而下降，但令人惊讶的是，人们对细胞骨架在正常衰老过程中的作用知之甚少。事实上，目前还不清楚肌动蛋白细胞骨架的调制是否能延长哺乳动物细胞的寿命。我们以酵母为模型系统，首次获得了肌动蛋白细胞骨架调控可以延长寿命的证据。我们实验室以前的研究揭示了肌动蛋白细胞骨架在控制线粒体运动和促进酵母子细胞遗传更合适的线粒体方面的作用，并揭示了这一过程的机制。同样重要的是，我们发现促进肌动蛋白的动态和功能通过线粒体依赖的机制延长了酵母的寿命和健康寿命。最后，我们获得了酵母中肌动蛋白细胞骨架随着年龄的增长经历结构、极化和功能下降的证据，并且在老化细胞中观察到的肌动蛋白缺陷类似于Sirtuin寿命调节家族的创始成员Sir2p缺失时观察到的缺陷。在R21阶段，我们将以酵母为模型系统，研究肌动蛋白细胞骨架功能随年龄增长而下降的机制。具体地说，我们将测试肌动蛋白细胞骨架组装的稳定性是否存在与年龄相关的下降，以及是否在通过调节Sir2p而延长或缩短寿命的酵母中观察到类似的变化。我们获得了肌动蛋白经历与年龄相关的翻译后修饰(PTM)的证据，并将确定这些PTM的性质和它们发生在肌动蛋白上的位置。最后，我们将测试肌动蛋白极化与年龄相关的下降是否是由于cdc42极化或活性的缺陷。 (一种保守的Rho蛋白和肌动蛋白调节蛋白)和/或福尔马林(它们介导肌动蛋白在极化细胞表面生长部位的聚合和组装，并被Cdc42招募到这些部位)。在R33阶段，我们将确定促进肌动蛋白细胞骨架的结构、极化和功能的干预措施或阻止与年龄相关的肌动蛋白PTM是否延长寿命和/或健康寿命。此外，我们还鉴定了一些基因，包括以前未曾描述过的开放阅读框架，它们在酵母遗传筛选中增强了肌动蛋白的结构和极性。我们将测试这些基因和其他肌动蛋白相关蛋白的调节是否可以延长寿命(R21期)，以及延长寿命基因调控肌动蛋白的机制(R33期)。由于肌动蛋白功能的下降发生在衰老的哺乳动物细胞、组织和器官中，稳定的肌动蛋白延长了线虫的寿命，这些研究将为理解与年龄相关的肌动蛋白细胞骨架的下降提供基础，并可能揭示在酵母和其他真核生物中促进肌动蛋白功能的寿命和健康控制的干预措施。