Developmental mechanisms of CNS pathology in mitochondrial disease

线粒体疾病中枢神经系统病理学的发育机制

• 批准号: 10296147
• 负责人: Simon C Johnson
• 金额: $ 47.13万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10296147
• 关键词: Affect; Age; Attenuated; Birth; Caenorhabditis elegans; Cardiovascular Diseases; Childhood; Clinical; Complex; Data; Defect; Development; Developmental Biology; Disease; Electron Transport; Environmental Exposure; Etiology; Event; FRAP1 gene; Functional disorder; Genetic; Goals; Growth; Health; Homologous Gene; Human; Human Pathology; Hypoxia; Individual; Intervention; Knockout Mice; Lead; Leigh Disease; Life; Link; Mediating; Metabolic; Metabolic Diseases; Metabolic dysfunction; Mitochondria; Mitochondrial Diseases; Modeling; Molecular; Mutation; Nematoda; Neurodegenerative Disorders; Neurologic; Neurologic Symptoms; Onset of illness; Organ; Pathogenesis; Pathology; Pathway interactions; Phenotype; Physiological; Role; Seizures; Sirolimus; Specificity; Symptoms; Syndrome; Testing; Treatment Efficacy; Work; acute symptom; age related; associated symptom; attenuation; base; experimental study; gene product; human model; in utero; insight; ketogenic diet; mTOR Inhibitor; mTOR inhibition; mitochondrial dysfunction; mouse model; neurodevelopment; novel; postnatal; postnatal development; postnatal period; preclinical study; prevent; therapy development; trait

Project Summary/Abstract Our long-term goal is to define the molecular and cellular mechanisms involved in the pathogenesis and complex clinical presentations of mitochondrial dysfunction. Our overall objective in the studies proposed here, which are a next step in pursuing this goal, is to define the relationship between development and onset of disease resulting from mitochondrial electron transport chain complex I (ETC CI) dysfunction. We hypothesize, based on substantial preliminary data, that some of the major neurologic sequelae of mitochondrial disease are mechanistically driven by the interaction between mitochondrial function and specific events in postnatal development. In particular, our preliminary data reveal a striking specificity to age of disease onset and, more telling, that treatment during a specific post-natal period is both necessary and sufficient for lasting benefits from rapamycin treatment, a well-validated intervention in pre-clinical studies of mitochondrial disease. Our experiments will take advantage of the Ndufs4(KO) mouse, apremier model of mitochondrial disease closely resembling human LS. In addition, we have generated a novel nematode model of LS which has a robust developmental phenotype and is defective in the C. elegans homologue of Ndufs4, lpd-5. We will use these models to define the role of postnatal neurodevelopment in the onset of neurological features of mitochondrial disease i) probe the interaction between development and onset of major neurological sequelae of disease ; ii) define the critical window in development for interventions targeting disease; iii) identifying genetic factors involved in developmental arrest associated with mitochondrial dysfunction in C. elegans. Ultimately, this work will advance our understanding of the role of mitochondria in developmental biology and help define the cellular and molecular pathogenesis of mitochondrial diseases. Relevance Genetic mitochondrial diseases involve an array of symptoms, can impact one organ or present as a multisystem disorder, are remarkably heterogeneous, and currently there are no proven treatments for mitochondrial disease of any etiology. A clear understanding of the pathogenesis of individual mitochondrial diseases is severely needed; the molecular, cellular, physiological, and developmental mechanisms underlying the complex clinical syndromes arising from primary genetic mitochondrial dysfunction have not been undefined.

项目摘要/摘要 我们的长期目标是定义与发病机理有关的分子和细胞机制 线粒体功能障碍的复杂临床表现。我们在提出的研究中的总体目标 在这里，这是实现这一目标的下一步，就是定义发展与发作之间的关系 线粒体电子传输链复合物I（ETC CI）功能障碍引起的疾病。我们 基于大量初步数据假设，线粒体的一些主要神经系统后遗症 疾病是由线粒体功能与特定事件之间的相互作用机械驱动的 产后发展。特别是，我们的初步数据揭示了对疾病年龄的特异性 而且，更明确地说，在特定的产后期间的治疗既需要持久 雷帕霉素治疗的益处，这是线粒体疾病临床前研究的验证良好的干预措施。 我们的实验将利用NDUFS4（KO）小鼠，线粒体疾病的APREMIER模型 类似于人类LS。此外，我们已经生成了具有强大的LS的新型线虫模型 发育表型，在NDUFS4，LPD-5的秀丽隐杆线虫同源物中有缺陷。我们将使用这些 定义产后神经发育在线粒体神经功能发作中的作用的模型 疾病i）探测主要神经系统后遗症发育与发作之间的相互作用； ii） 定义针对疾病的干预措施开发的关键窗口； iii）识别遗传因素 参与与秀丽隐杆线虫中线粒体功能障碍有关的发育停滞。最终，这项工作 将促进我们对线粒体在发育生物学中的作用的理解，并有助于定义细胞 线粒体疾病的分子发病机理。 关联 遗传线粒体疾病涉及一系列症状，可能会影响一个器官或作为多系统 疾病，非常异质，目前尚无对线粒体疾病的良好治疗方法 任何病因。对个体线粒体疾病的发病机理的清晰了解很严重 需要；复杂临床的基础的分子，细胞，生理和发育机制 原发性线粒体功能障碍引起的综合征尚未未定。