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

• 批准号: 9979108
• 负责人: Brian Matthew Zid
• 金额: $ 22.63万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9979108
• 关键词: Address; Affect; Age; Aging; Alzheimer' 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; insight; link protein; live cell imaging; messenger ribonucleoprotein; novel; novel strategies; predictive marker; protein aggregation; proteostasis; sarcoma; stressor

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/摘要 神经退行性疾病是一类导致进行性神经退行性疾病的不治之症。 神经元细胞的变性。最近的研究指出了RNA结合蛋白在衰老中的作用， 相关的神经退行性疾病：由于许多RNA结合蛋白具有聚集倾向， 本质上无序的区域，它们聚集在各种病理性包涵体中， 神经退行性疾病，以及许多RNA结合蛋白的突变已与 神经退行性疾病对于许多与神经退行性疾病有关的RNA结合蛋白， 它们在应激条件下也浓缩成mRNP颗粒。这阵法 应激期间的mRNP颗粒对细胞是有益的，因为这些颗粒的破坏使细胞对应激敏感。 各种压力源。我们的假设是，mRNP颗粒最初形成为无毒的，潜在的 有益的结构在老化过程中，但他们经历了一个病理性的转变，导致 细胞死亡。该提案试图建立一个模型系统，用于这种病理性转变， 酵母与微流体组合，以跟踪mRNP颗粒的形成和转变， 衰老为了实现这一目标，我们将（目标1）建立在我们的初步数据探索致病性 使用微流体和荧光显微镜跟踪单个酵母的大年龄诱导的mRNP颗粒 在它们的整个生命周期中。其次，我们将（目标2）确定这种病理性的标志物， 通过测量老化引起的材料状态和大分子组成的变化， mRNP颗粒。从长远来看，这些标记将有助于阐明这一机制的细节， 过渡这个系统将建立一个新的范式，以了解如何 mRNP颗粒可以从无毒的、潜在有益的结构转变为病理性包涵体 导致细胞退化由于许多基因和途径是保守的，从酵母到 哺乳动物，包括影响衰老的途径，这项研究可能会指出新的目标，以帮助 改善人类的神经退行性疾病。