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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：
9190230
负责人：
Ryo Higuchi-Sanabria
金额：
$ 5.25万
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/9190230
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 Exocytosis 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 Molecular Profiling Movement Muscle Muscle Cells Muscle Fibers Myopathy Nature Nerve Degeneration Organelles Organism Pathway interactions Play Premature aging syndrome Proteins Regulation Research Role Saccharomyces cerevisiae Staging Staining method Stains Stress Supporting Cell System T-Lymphocyte Testing Therapeutic Intervention Tissues Vesicle Work Yeasts abstracting age related aged biological adaptation to stress cell type cellular imaging functional decline heat shock transcription factor imaging modality interest knock-down live cell imaging loss of function mitochondrial fitness mutant novel novel strategies overexpression prevent recombinase response screening 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.

项目总结/文摘