The Collapse of Proteostasis during Aging is Mediated by Cytoskeletal Actin Functions

衰老过程中蛋白质稳态的崩溃是由细胞骨架肌动蛋白功能介导的

• 批准号: 9902275
• 负责人: Andrew G Dillin
• 金额: $ 32.19万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9902275
• 关键词: Acceleration; Actins; Affect; Age; Age of Onset; Aging; Animals; Behavior; Biochemical; Biological Assay; Caenorhabditis elegans; Calmodulin; Cell Aging; Cell physiology; Cells; Cellular Stress; Complex; Cytoskeleton; Data; Deterioration; Disease; Distal; Elderly; Endocrine; Ensure; Filament; Gene Chips; Gene Expression; Genes; Genetic; Genetic Screening; Genetic Transcription; Growth; HSF1; Health; Homeostasis; Image; Imaging Techniques; Impairment; Individual; Intestines; Longevity; Maintenance; Mediating; Microfilaments; Microscopy; Molecular Chaperones; Monitor; Nematoda; Neurons; Onset of illness; Organism; Pathway interactions; Physiological; Play; Process; Protein Engineering; Proteins; Proteomics; Regulation; Resistance; Role; Series; Signal Transduction; Sorting - Cell Movement; Stress; Structure; Tissues; Toxic effect; Transportation; Troponin C; Up-Regulation; Variant; Work; age related; alpha Actin; biological adaptation to stress; cell age; cell component structure; cell motility; cofilin; design; functional decline; functional restoration; genetic analysis; genetic manipulation; healthspan; heat shock transcription factor; in vivo; in vivo imaging; innovation; misfolded protein; normal aging; overexpression; profilin; protein aggregation; protein degradation; protein folding; proteostasis; proteotoxicity; response; thermal stress; transcription factor; transcriptome sequencing

The conserved heat shock transcription factor-1 (HSF-1) is essential to cellular stress resistance and life-span determination. The canonical function of HSF-1 is to regulate a network of genes encoding molecular chaperones that protect proteins from damage caused by extrinsic environmental stress or intrinsic age-related deterioration. In Caenorhabditis elegans, we discovered a modified HSF-1 strain that increased stress resistance and longevity without enhanced chaperone induction. Intriguingly, both modified HSF-1 and wild type HSF-1 were instead capable of increasing expression of an array of actin regulating genes. These data suggest that HSF-1 has a prominent role in actin cytoskeletal integrity. Surpassingly, upregulation of at least one of these actin components was alone sufficient to increase stress resistance and life span. We hypothesize that a loss in actin homeostasis occurs during the aging process, and that this loss is driven by the inability for HSF-1 to normally mount a response to protect actin from stress in aging cells. In this proposal, we will explore how actin homeostasis becomes compromised during normal aging, and whether the activity of HSF-1 will protect the cells from age-onset declines in function. We will use state-of-the-art, in vivo imaging techniques alongside innovative biochemical analyses to monitor changes in actin structure and dynamics both spatial and temporally. We predict that forced expression of hsf-1 in geriatric animals will restore the function of the actin cytoskeleton, protecting the cell from age-onset damage and extending lifespan. We will further explore the possibility that hsf-1 works as a part of a team of additional stress-responsive proteins designed to manage a “actin cytoskeletal stress response” that be compromised with age, and propose a series of genetic screens to identify other actin-regulatory factors. Finally, we will explore the idea that changes in actin dynamics must be coordinated across tissues and cells, suggesting a role for hsf-1 in the endocrine mediated regulation of actin dynamics. We will leave this work with a newfound understanding of the role of actin homeostasis plays in many of the destructive diseases seen in older individuals.

保守的热休克转录因子-1(HSF-1)是细胞抵抗应激和延长寿命所必需的 决心。HSF-1的典型功能是调节编码分子的基因网络 保护蛋白质免受外在环境应激或内在年龄相关损伤的伴侣 恶化。在秀丽隐杆线虫中，我们发现了一种改良的HSF-1菌株，它增加了压力 在没有增强伴侣诱导的情况下，抗性和寿命。耐人寻味的是，改良的HSF-1和野生型 相反，HSF-1型能够增加一系列肌动蛋白调节基因的表达。这些数据 提示HSF-1在肌动蛋白细胞骨架完整性中具有显著作用。 更重要的是，仅这些肌动蛋白成分中至少一种的上调就足以增加压力 抵抗力和寿命。我们假设在衰老过程中会发生肌动蛋白动态平衡的丧失，并且 这种损失是由于HSF-1不能正常地启动反应来保护肌动蛋白免受应激 老化的细胞。在这项提案中，我们将探讨肌动蛋白的动态平衡是如何在正常情况下被破坏的。 衰老，以及HSF-1的活性是否能保护细胞免受年龄起病的功能衰退的影响。我们将使用 最先进的活体成像技术与创新的生化分析相结合，以监测 肌动蛋白的空间和时间结构和动力学。我们预测HSF-1在老年人中的强制表达 动物将恢复肌动蛋白细胞骨架的功能，保护细胞免受年龄的损害和 延长寿命。我们将进一步探索HSF-1作为一个额外团队的一部分工作的可能性 应激反应蛋白设计用于管理受损的“肌动蛋白细胞骨架应激反应” 随着年龄的增长，并提出了一系列基因筛查，以确定其他肌动蛋白调节因素。最后，我们会 探索肌动蛋白动力学的变化必须在组织和细胞之间协调的想法，建议 Hsf-1在内分泌调节肌动蛋白动力学中的作用。我们将把这项工作留给新发现的人 了解肌动蛋白动态平衡在老年人许多破坏性疾病中的作用 个人。