The role of mTOR in mitochondrial encephalopathy

mTOR 在线粒体脑病中的作用

• 批准号: 9920237
• 负责人: Simon C Johnson
• 金额: $ 24.9万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-19 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9920237
• 关键词: Affect; Attenuated; Brain; Cell Compartmentation; Cell Death; Cell physiology; Cells; Characteristics; Childhood; Clinical; Complex; Data; Development; Diagnosis; Disease; Disease model; Electron Transport; Elements; Encephalopathies; Etiology; Event; FRAP1 gene; Functional disorder; Genes; Genetic; Goals; Human; Human Genetics; Hyperactive behavior; Incidence; Individual; Knockout Mice; Lead; Leigh Disease; Lesion; Longevity; Mediating; Metabolism; Mitochondria; Mitochondrial Diseases; Modeling; Modification; Molecular; Mutation; Neurologic; Nuclear; Nutrient; Organ; Oxidative Stress; Pathogenesis; Pathology; Pathway interactions; Pharmacology; Phosphorylation; Process; Production; Proteins; Proteome; Role; Severities; Signal Pathway; Signal Transduction; Specificity; Symptoms; Testing; Training; Work; attenuation; career; career development; cell type; detection of nutrient; effective therapy; experimental study; human disease; human model; improved; insight; mitochondrial dysfunction; mouse model; neurodevelopment; neurotoxic; novel therapeutics; respiratory; virtual

Project Summary/Abstract Our overarching goal is to define the molecular mechanisms underpinning the pathogenesis of mitochondrial disease. Our overall objective in the studies proposed here, which represent the next step in pursuing this goal, is to characterize the pathogenesis of subacute necrotizing encephalopathy and define the role of mTOR in this disease using the Ndufs4(KO) model. Genetic mitochondrial diseases include an array of symptoms, may affect one organ or present as a multisystem disorder, and are remarkably heterogeneous in severity. There are few good models for these diseases and no effective treatment options for mitochondrial disease of any etiology. A clear understanding of the pathogenesis of individual mitochondrial diseases is severely needed; the molecular mechanisms underlying their multiple distinct clinical manifestations are currently unknown. Subacute necrotizing encephalomyelopathy, or Leigh syndrome (LS), is a fatal pediatric mitochondrial disease. Characteristic features of LS include region specific necrotizing lesions of the brain. Though these lesions are the major defining feature of LS, virtually nothing is known of initiating events, what underlies the spatial and temporal specific aspects of the disease, or why some regions of the CNS are inexplicably spared. Our recent work has shown that inhibition of the nutrient sensing signaling complex mTOR attenuates LS in a mouse model, but the mechanisms underlying the benefit are unknown. The goal of this proposal is to define the pathogenesis of LS and the role of mTOR in this disease. We hypothesize that the neurological lesions characteristic of LS result from region and cell-type specific effects of mitochondrial dysfunction, and that mTOR inhibition acts through a discreet downstream neurotoxic pathway. Our experiments will take advantage of the Ndufs4(KO) mouse model of LS, a premier model of human genetic mitochondrial disease which closely resembles human LS. Using this model, we will use characterize the cellular and molecular pathogenesis of neurological lesions in LS by i) identifying the earliest type of cell death and ii) the CNS cell types first lost in lesion formation, iii) defining the region, cell, and cell compartment specificity of phospho-proteome changes during CNS lesion formation, and iv) testing the role of key mTOR regulated pathways in LS using pharmacological approaches. Ultimately, this work will expose basic molecular features of LS and mitochondrial disease in general. In addition, the career development and training components of this proposal will provide key elements for my successful transition to an independent career.

项目摘要/摘要 我们的总体目标是定义基于发病机理的分子机制 线粒体疾病。我们在这里提出的研究中的总体目标，这代表了下一步 追求这一目标是表征亚急性坏死性脑病的发病机理，并定义 使用NDUFS4（KO）模型，MTOR在该疾病中的作用。 遗传线粒体疾病包括一系列症状，可能会影响一个器官或作为一个器官 多系统障碍，严重程度非常异质。这些型号很少 疾病和任何病因的线粒体疾病没有有效的治疗选择。对 严重需要单个线粒体疾病的发病机理；分子机制 目前未知它们的多种不同临床表现。 亚急性坏死性脑瘤病（LS）是一种致命的小儿线粒体疾病。 LS的特征包括区域特异性坏死病变。虽然这些病变是 LS的主要定义特征，几乎没有任何启动事件，是什么是空间和空间的基础 疾病的时间特定方面，或者为什么中枢神经系统的某些区域被莫名其妙。我们最近 工作表明，抑制营养感应信号传导复合物mTOR会减弱小鼠中的LS 模型，但是益处的基础机制尚不清楚。 该提案的目的是定义LS的发病机理和MTOR在该疾病中的作用。我们 假设LS的神经病变特征是由区域和细胞类型的特异性效应引起的 线粒体功能障碍，该MTOR抑制作用通过谨慎的下游神经毒性起作用 路径。 我们的实验将利用LS的NDUFS4（KO）小鼠模型，这是人类的主要模型 遗传线粒体疾病与人类密切相似。使用此模型，我们将使用特征 LS中神经病变的细胞和分子发病机理，通过i）识别最早的细胞类型 死亡和II）CNS细胞类型首先在病变形成中丢失，iii）定义区域，细胞和细胞室 CNS病变形成期间磷酸化 - 蛋白质变化的特异性，iv）测试关键MTOR的作用 使用药理方法在LS中调节途径。最终，这项工作将暴露基本分子 总体而言，LS和线粒体疾病的特征。此外，职业发展和培训 该提案的组成部分将为我成功过渡到独立职业的关键要素。