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 我们的首要目标是确定支持本病发病的分子机制。 线粒体疾病。我们在这里提出的研究的总体目标，代表着 追求这一目标，是为了表征亚急性坏死性脑病的发病机制，并确定 利用Ndufs4(KO)模型研究mTOR在本病中的作用。 遗传性线粒体疾病包括一系列症状，可能影响一个器官或表现为 多系统紊乱，严重程度明显不同。对于这些人来说，好的模式很少 对于任何病因的线粒体疾病，没有有效的治疗选择。对……的清醒认识 个体线粒体疾病的发病机制是迫切需要的；分子机制 其潜在的多种不同的临床表现目前尚不清楚。 亚急性坏死性脑脊髓病，或Leigh综合征(LS)，是一种致命的儿科线粒体疾病。 LS的特征包括脑部特定区域的坏死性病变。尽管这些损伤是 LS的主要定义特征是，对启动事件几乎一无所知，空间和空间上的 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莫名其妙地幸免于难。我们最近 研究表明，抑制营养感应信号复合体mTOR可以减弱小鼠的LS 模型，但这种益处背后的机制尚不清楚。 这项建议的目的是明确LS的发病机制和mTOR在该疾病中的作用。我们 假设LS的神经损害是由区域和细胞类型特异性效应引起的 线粒体功能障碍，mTOR抑制通过一种谨慎的下游神经毒素起作用 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 与人类LS极为相似的遗传性线粒体疾病。使用此模型，我们将使用Characterize LS神经损害的细胞和分子发病机制：I)鉴定最早的细胞类型 死亡和ii)首先在病变形成过程中丢失的中枢神经系统细胞类型，iii)定义区域、细胞和细胞室 中枢神经系统损伤形成过程中磷酸化蛋白质组变化的特异性，以及iv)检测关键mTOR的作用 用药理学方法调节LS中的通路。最终，这项工作将揭示基本的分子 LS和线粒体疾病的一般特征。此外，职业发展和培训 这项提案的组成部分将为我成功过渡到独立职业生涯提供关键要素。