Preventing and reversing mitochondrial Leigh syndrome with hypoxia

摘要 利综合征是线粒体疾病最常见的儿科表现，其特征是 大脑深部灰质两侧对称的坏死性病变。超过80种不同的基因- 无论是在核DNA中还是在线粒体DNA中，都可以成为Leigh综合征的基础，但我们还没有批准 治疗这种致命疾病的药物。我们最近发现，低氧--低氧--可以缓冲各种形式 人类细胞、蠕虫模型和小鼠线粒体功能障碍的研究。事实上，呼吸低氧是能够充分 预防Leigh综合征Ndufs4KO小鼠模型的脑部疾病，当低氧呼吸 在患有晚期疾病的小鼠中开始治疗，我们能够逆转神经退化。我们不会 了解呼吸缺氧能够逆转疾病的全部机制，能否辨别出细小 能够针对这些机制逆转疾病的分子药物，以及低氧治疗是否会 推广到其他线粒体脑病的小鼠模型。在本应用程序中，我们将应用尖端技术 单细胞基因组学、蛋白质组学、线粒体DNA编辑和小鼠生理学研究以解决这三个问题 挑战。我们预计，该项目可能对理解基本的 神经退行性变和神经再生的生物学，以及对治疗和治疗的重要未来意义 线粒体疾病患者的管理。

ABSTRACT Leigh syndrome is the most common pediatric manifestation of mitochondrial disease and is characterized by bilaterally symmetric, necrotic lesions in the deep gray matter of the brain. More than 80 different genes – either in the nuclear DNA or mitochondrial DNA – can underlie Leigh syndrome, yet we do not have approved medicines for this lethal disease. We recently discovered that low oxygen – hypoxia – can buffer diverse forms of mitochondrial dysfunction in human cells, worm models, and mice. In fact, breathing hypoxia is able to fully prevent brain disease in the Ndufs4 KO mouse model of Leigh syndrome, and when hypoxic breathing is initiated in mice with advanced, end-stage disease, we are able to reverse neurodegeneration. We do not know the full mechanism by which breathing hypoxia is able reverse disease, whether we can identify small molecule drugs that can target these mechanisms to reverse disease, and whether hypoxia therapy this generalize to other mouse models of mitochondrial brain disease. In this application, we will apply cutting edge single cell genomics, proteomics, mtDNA editing, and mouse physiology studies to address these three challenges. We anticipate that this project could have important implications for understanding the basic biology of neurodegeneration and neuroregeneration, with important future implications for the treatment and management of patients with mitochondrial disease.