Developmental mechanisms of CNS pathology in mitochondrial disease

项目总结/摘要 我们的长期目标是确定参与发病机制的分子和细胞机制， 线粒体功能障碍的复杂临床表现。我们建议研究的整体目标 在这里，这是追求这一目标的下一步，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）功能障碍引起的疾病。我们 基于大量的初步数据，假设线粒体损伤的一些主要神经系统后遗症 疾病是由线粒体功能和特定事件之间的相互作用机制驱动的， 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 而且，更能说明问题的是，在特定的产后时期进行治疗对于持久的 从雷帕霉素治疗中获益，这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Ndufs 4（KO）小鼠，一种线粒体疾病的近似模型， 类似于人的LS此外，我们还生成了一个新的LS线虫模型，该模型具有鲁棒性， 发育表型，并在C. Ndufs 4的elegans同源物，lpd-5。我们将会用这些 模型来定义出生后神经发育在线粒体神经功能发作中的作用 疾病i）探索疾病的主要神经系统后遗症的发展和发作之间的相互作用; ii） 确定制定针对疾病的干预措施的关键窗口; iii）确定遗传因素 参与与C.优雅最终，这项工作 这将促进我们对线粒体在发育生物学中作用的理解，并有助于定义细胞内的线粒体。 以及线粒体疾病的分子发病机制。 相关性 遗传性线粒体疾病涉及一系列症状，可以影响一个器官或作为多系统存在 疾病，是显着异质性，目前还没有证明治疗线粒体疾病 任何病因。对单个线粒体疾病的发病机制的清楚理解是严重的， 需要;分子，细胞，生理和发育机制的复杂的临床 由原发性遗传性线粒体功能障碍引起的综合征尚未确定。

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.