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) 对于细胞抗应激能力和寿命至关重要 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压力或内在年龄相关的损害的伴侣 在秀丽隐杆线虫中，我们发现了一种经过修饰的 HSF-1 菌株，它会增加压力。 有趣的是，修饰的 HSF-1 和野生的都具有抗性和寿命。 HSF-1 型反而能够增加一系列肌动蛋白调节基因的表达。 表明 HSF-1 在肌动蛋白细胞骨架完整性中具有重要作用。 令人惊奇的是，这些肌动蛋白成分中至少一种的上调就足以增加压力 我们认为衰老过程中会发生肌动蛋白稳态的丧失，并且 这种损失是由于 HSF-1 无法正常做出反应来保护肌动蛋白免受压力造成的 在本提案中，我们将探讨正常情况下肌动蛋白稳态如何受到损害。 衰老，以及 HSF-1 的活性是否会保护细胞免受年龄增长带来的功能衰退。 最先进的体内成像技术以及创新的生化分析来监测 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，保护细胞免受年龄损伤 我们将进一步探索 hsf-1 作为其他团队的一部分发挥作用的可能性。 旨在管理受到损害的“肌动蛋白细胞骨架应激反应”的应激反应蛋白 随着年龄的增长，并提出一系列遗传筛选来识别其他肌动蛋白调节因素。 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，表明 hsf-1 在内分泌介导的肌动蛋白动力学调节中的作用我们将用一个新发现来结束这项工作。 了解肌动蛋白稳态在老年人常见的许多破坏性疾病中的作用 个人。