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.

项目概要/摘要 我们的长期目标是确定发病机制和相关的分子和细胞机制。 线粒体功能障碍的复杂临床表现。我们提出的研究的总体目标 实现这一目标的下一步是定义发展和发病之间的关系 线粒体电子传递链复合物 I (ETC CI) 功能障碍导致的疾病。我们 根据大量初步数据，假设线粒体的一些主要神经系统后遗症 疾病在机制上是由线粒体功能与特定事件之间的相互作用驱动的 产后发育。特别是，我们的初步数据揭示了疾病发病年龄的惊人特异性 更能说明问题的是，在特定的产后时期进行治疗对于持久治疗来说既是必要的也是充分的。 受益于雷帕霉素治疗，雷帕霉素治疗是线粒体疾病临床前研究中经过充分验证的干预措施。 我们的实验将利用Ndufs4（KO）小鼠，线粒体疾病的高级模型密切 类似于人类LS。此外，我们还生成了一种新型的 LS 线虫模型，该模型具有鲁棒性 发育表型，并且 Ndufs4、lpd-5 的线虫同源物有缺陷。我们将使用这些 定义出生后神经发育在线粒体神经学特征发生中的作用的模型 疾病 i) 探讨疾病主要神经系统后遗症的发展和发作之间的相互作用；二） 确定针对疾病的干预措施制定的关键窗口； iii) 识别遗传因素 参与与线虫线粒体功能障碍相关的发育停滞。最终，这部作品 将增进我们对线粒体在发育生物学中的作用的理解，并帮助定义细胞 和线粒体疾病的分子发病机制。 关联 遗传性线粒体疾病涉及一系列症状，可以影响一个器官或表现为多系统 紊乱，具有显着的异质性，目前还没有经过证实的线粒体疾病治疗方法 任何病因学。清楚地了解个体线粒体疾病的发病机制非常重要 需要；复杂临床背后的分子、细胞、生理和发育机制 由原发性遗传性线粒体功能障碍引起的综合征尚未明确。