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（由适用提供）：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护，连接和形状，肌肉收缩，细胞信号传导和细胞因子。尽管肌动蛋白功能在包括骨骼和心肌以及免疫系统在内的所有系统中都有与年龄相关的下降很干净，但对细胞骨架的作用确实鲜为人知，但尚不清楚肌动蛋白细胞骨骼的调节是否可以在哺乳动物细胞中延长寿命。我们获得了第一个证据，表明肌动蛋白细胞骨架的调节可以使用酵母作为模型系统延长寿命。我们实验室的先前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发子细胞对拟合拟合的线粒体的遗传中的作用，并发现了该过程的基础机制。同样重要的是，我们发现促进肌动蛋白动力学和功能通过线粒体依赖性机制扩展了酵母的寿命和HealthSpan。最后，我们获得了证据表明，肌动蛋白细胞骨架随着年龄的增长而在酵母中的结构，极化和功能下降，并且在旧细胞中观察到的肌动蛋白的缺陷与Sir2p删除后观察到的缺陷相似，Sir2p的创始成员是Lifespan调节剂的Sirtuin家族的创始成员。在R21阶段，我们将使用酵母作为模型系统研究肌动蛋白细胞骨架的功能下降的机制。具体而言，我们将测试在肌动蛋白细胞骨架的稳定性O组装中是否存在年龄相关的下降，以及是否在通过调节SIR2P的调节中延长或降低寿命的酵母中观察到了类似的变化。我们获得了肌动蛋白经历年龄相关的翻译后修饰（PTM）的证据，并将确定这些PTMS的性质以及肌动蛋白发生的位置。最后，我们将测试与年龄相关的肌动蛋白极化下降是由于Cdc42的极化或活性缺陷所致 （组成的Rho蛋白和肌动蛋白调节剂）和/或formins（在极化细胞表面生长的位点介导肌动蛋白聚合和组装，并通过CDC42募集到这些位点）。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是肌动蛋白蛋白的年龄相关PTM延长寿命和/或HealthSpan。此外，我们确定了基因，包括先前未表征的开放式阅读框，从而增强了酵母遗传筛选中的肌动蛋白结构和极性。我们将测试这些基因和其他与肌动蛋白相关的蛋白的调节是否可以延长寿命（R21相），以及通过延伸寿命 - 延伸基因（R33期）调节肌动蛋白调节的机制。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，并且稳定肌动蛋白延长了秀丽隐杆线虫的寿命，因此这些研究将为理解肌动蛋白细胞骨架中与年龄相关的下降提供基础，并可能揭示在酵母和其他Eukaryotes中促进肌动蛋白和Healthspan Control的肌动蛋白功能的干预措施。