Developmental mechanisms of CNS pathology in mitochondrial disease

项目摘要/摘要 我们的长期目标是确定分子和细胞机制参与发病机制和 线粒体功能障碍的复杂临床表现。我们在研究中的整体目标是 这里，是追求这一目标的下一步，是定义发展和发病之间的关系 由线粒体电子传递链复合体I(ETC CI)功能障碍引起的疾病。我们 基于大量初步数据的假设，线粒体的一些主要神经后遗症 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 后天发育。特别是，我们的初步数据显示了疾病发病年龄的显著特异性。 而且，更能说明问题的是，在特定的产后期进行治疗对于持久是必要的，也是充分的。 受益于雷帕霉素治疗，这是一种在线粒体疾病的临床前研究中得到充分验证的干预措施。 我们的实验将利用Ndufs4(KO)小鼠，这是线粒体疾病的主要模型 看起来像人类的LS。此外，我们还生成了一种新的LS线虫模型，该模型具有较强的鲁棒性 发育表型，在线虫Ndufs4，LPD-5的同源物中是缺陷的。我们将使用这些 确定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 疾病一)探讨疾病的主要神经后遗症的发生和发展之间的相互作用；二) 确定针对疾病的干预措施发展的关键窗口；三)确定遗传因素 参与线虫线粒体功能障碍相关的发育停滞。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制。 相关性 遗传性线粒体疾病涉及一系列症状，可影响一个器官或呈现为多系统 线粒体疾病具有显著的异质性，目前还没有被证实的治疗线粒体疾病的方法。 任何原因造成的。对个别线粒体疾病的发病机制有明确的认识是严重的 所需；复杂临床的分子、细胞、生理和发育机制 由原发遗传性线粒体功能障碍引起的综合征并不是不确定的。

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.