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A model system for pathological transitions of RNA-binding protein aggregates

RNA结合蛋白聚集体病理转变的模型系统

基本信息

批准号：
10263214
负责人：
Brian Matthew Zid
金额：
$ 19.3万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10263214
关键词：
Address Affect Age Aging Alzheimer&apos s Disease Amyotrophic Lateral Sclerosis Behavior Biological Markers Biological Models Biophysics Cell Death Cell physiology Cells Chemicals Communities Cytoplasmic Granules Data Disease Genes Goals Human Individual Link Liquid substance Longevity Mammals Mass Spectrum Analysis Measures Methods Microfluidic Microchips Microfluidics Microscopy Molecular Mothers Mutation Nature Nerve Degeneration Neurodegenerative Disorders Pathogenicity Pathologic Pathway interactions Phase Transition Phenotype Physiological Process Proteins RNA-Binding Proteins Research Research Proposals Resources Role Saccharomyces cerevisiae Saccharomycetales Solid Stress Structure System Testing Time Work Yeasts age related neurodegeneration aged base cell age daughter cell fused in sarcoma insight link protein live cell imaging messenger ribonucleoprotein novel novel strategies predictive marker protein aggregation proteostasis stressor

项目摘要

Project Summary/Abstract Age-related neurodegenerative diseases are a class of incurable diseases that result in the progressive degeneration of neuronal cells. Recent research has pointed to a role for RNA-binding proteins in age- related neurodegenerative diseases: as many RNA-binding proteins have aggregation-prone intrinsically disordered regions, they accumulate in pathological inclusions of various neurodegenerative diseases, and mutations in a number of RNA-binding proteins have been linked to neurodegenerative diseases. For many RNA-binding proteins linked to neurodegenerative diseases they also become concentrated into mRNP granules during stressful conditions. This formation of mRNP granules during stress is beneficial to cells, as disruption of these granules sensitizes cells to a variety of stressors. Our hypothesis is that mRNP granules initially form as non-toxic, potentially beneficial structures during the aging process, but that they undergo a pathological transition that leads to cell death. This proposal seeks to establish a model system for this pathological transition using yeast in combination with microfluidics to follow the formation and transition of mRNP granules during aging. To accomplish this, we will (Aim 1) build on our preliminary data exploring the pathogenicity of large age-induced mRNP granules using microfluidics and fluorescent microscopy to follow single yeast cells across their entire lifespan. Secondly, we will (Aim 2) identify markers for this pathological transition by measuring changes in the material state and macromolecular composition of age-induced mRNP granules. In the long term these markers will help to elucidate the mechanistic details of this transition. Together this system will establish a new paradigm to understand basic details on how mRNP granules can transition from non-toxic, potentially beneficial structures to pathological inclusions that drive the degeneration of cells. As many genes and pathways are conserved from yeast to mammals, including pathways that affect aging, this research may point to new targets to help ameliorate neurodegenerative diseases in humans.

项目总结/文摘