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.

项目概要/摘要 我们的首要目标是确定支持疾病发病机制的分子机制 线粒体疾病。我们在此提出的研究的总体目标，代表了下一步 为了实现这一目标，我们的目标是描述亚急性坏死性脑病的发病机制，并定义亚急性坏死性脑病的发病机制。 使用 Ndufs4(KO) 模型观察 mTOR 在这种疾病中的作用。 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 多系统疾病，并且严重程度存在显着差异。这些方面很少有好的模型 疾病，并且没有针对任何病因的线粒体疾病的有效治疗方案。清楚地了解 迫切需要了解个体线粒体疾病的发病机制；分子机制 目前尚不清楚其多种不同临床表现的背后。 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 的特征包括大脑区域特异性坏死性病变。虽然这些损伤是 LS 的主要定义特征是，几乎对起始事件一无所知，空间和空间的基础是什么？ 该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。我们最近的 研究表明，抑制营养传感信号复合物 mTOR 可减弱小鼠的 LS 模型，但其益处背后的机制尚不清楚。 该提案的目标是明确 LS 的发病机制以及 mTOR 在该疾病中的作用。我们 假设 LS 的神经损伤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，并且 mTOR 抑制通过谨慎的下游神经毒性起作用 途径。 我们的实验将利用 LS 的 Ndufs4(KO) 小鼠模型，这是人类的首要模型 遗传性线粒体疾病，与人类 LS 非常相似。使用这个模型，我们将使用特征 LS 神经损伤的细胞和分子发病机制 i) 识别最早的细胞类型 死亡和 ii) CNS 细胞类型在病变形成中首先丢失，iii) 定义区域、细胞和细胞区室 CNS 病变形成过程中磷酸蛋白质组变化的特异性，以及 iv) 测试关键 mTOR 的作用 使用药理学方法调节 LS 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 该提案的组成部分将为我成功过渡到独立职业提供关键要素。