The Cytoskeletal Stress Response: A Novel Facet to Protecting Cell Integrity during Aging

细胞骨架应激反应：衰老过程中保护细胞完整性的一个新方面

基本信息

批准号：
9474556
负责人：
Ryo Higuchi-Sanabria
金额：
$ 5.9万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9474556
关键词：
Actins Address Adult Affect Age Aging Aging-Related Process Animal Model Animals Applications Grants Architecture Attention Autophagocytosis Axonal Transport Biochemical Caenorhabditis elegans Cell physiology Cells Cellular Stress Response Cessation of life Charge Clinical Cobalt Cytoskeletal Modeling Cytoskeleton Data Defect Disease Disease model Elderly Endocytosis Endoplasmic Reticulum Enterobacteria phage P1 Cre recombinase Exocytosis Expression Profiling F-Actin Failure Fiber Genes Goals Health Heat-Shock Response Homeostasis Image Immunofluorescence Immunologic Libraries Link Longevity Maintenance Mammals Maps Measures Mediating Messenger RNA Methods Mitochondria Modeling Molecular Molecular Chaperones Movement Muscle Muscle Cells Muscle Fibers Myopathy Nature Nerve Degeneration Organelles Organism Pathway interactions Play Premature aging syndrome Proteins Regulation Research Role Saccharomyces cerevisiae Stains Stress Supporting Cell System T-Lymphocyte Testing Therapeutic Intervention Tissues Vesicle Work Yeasts age related aged biological adaptation to stress cell type cellular imaging functional decline heat shock transcription factor imaging approach imaging modality interest knock-down live cell imaging loss of function mitochondrial fitness muscle aging mutant new therapeutic target novel novel strategies overexpression prevent response screening synergism transcription factor

项目摘要

Project Summary/Abstract This grant proposal seeks to identify the first known cytoskeleton-specific stress response and the potential regulators of this pathway. Previous work in yeast has identified an age-associated decline in cytoskeletal function and its implications in lifespan, while recent work in C. elegans have identified HSF-1 in mediating a protective role in cytoskeletal integrity. Marrying these findings, we propose to characterize both systemic and tissue-specific cytoskeletal decline as a function of age in the multicellular model organism, C. elegans. Next, we would like to identify the key players working both in synergy or independently of HSF-1 in protecting cytoskeletal integrity under stress and aging. Finally, we can determine whether the cytoskeletal stress response itself declines over age, as many stress response pathways do – including mitochondrial, endoplasmic reticulum, and cytoplasmic – and whether ectopic activation can rescue cytoskeletal function in advanced age. We will employ both biochemical and imaging methods to test our hypotheses. We propose to study cytoskeletal function by imaging of actin using LifeAct. In addition, we will purify actin proteins in a tissue- specific manner and study their function in worms at various stages of adulthood. Finally, we propose to perform a candidate screen of 400 transcription factors to identify novel regulators of cytoskeletal function. Here, endocytosis and organization of muscle fibers will be used as a readout for cytoskeletal integrity and function. At the culmination of this study, we will have characterized the cytoskeletal stress response as a function of age. Moving forward, this will open exciting avenues of research in continuing to map out the mechanistic pathway of the cytoskeletal stress response, as well as identifying the conservation of this mechanism in mammals and disease models.

项目摘要/摘要该赠款提案旨在确定第一个已知的细胞骨架特异性压力反应和该途径的潜在调节剂。先前在酵母中的工作已经确定了与年龄相关的下降细胞骨架功能及其在寿命中的影响，而秀丽隐杆线虫最近的工作已经确定了HSF-1 介导细胞骨架完整性中受保护的作用。嫁给这些发现，我们建议既表征全身和组织特异性细胞骨骼下降随多细胞模型生物体中年龄的函数C. 秀丽隐杆线。接下来，我们想确定在协同作用或独立于HSF-1中工作的关键参与者在压力和衰老下保护细胞骨架完整性。最后，我们可以确定细胞骨架是否压力反应本身随着年龄的增长而下降，就像许多压力反应途径一样 - 包括线粒体，内质网和细胞质 - 以及异位激活是否可以挽救细胞骨架功能高龄。我们将采用生化和成像方法来检验我们的假设。我们建议学习通过使用LIFEACT对肌动蛋白进行成像，细胞骨架功能。此外，我们将纯化组织中的肌动蛋白在成年的各个阶段，在蠕虫中的特定方式并研究了它们的功能。最后，我们建议执行400个转录因子的候选屏幕，以鉴定细胞骨架功能的新调节剂。在这里，肌肉纤维的内吞和组织将用作细胞骨架完整性和功能。在这项研究的高潮中，我们将将细胞骨架应激反应表征为一种年龄的功能。展望未来，这将开放令人兴奋的研究途径，以继续绘制细胞骨架应力反应的机械途径，并确定对此的保护哺乳动物和疾病模型的机制。