Preventing and reversing mitochondrial Leigh syndrome with hypoxia

预防和逆转缺氧线粒体利氏综合征

• 批准号: 10337378
• 负责人: Vamsi Krishna Mootha
• 金额: $ 63.09万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10337378
• 关键词: Address; Age; Air; Altitude; Anemia; Applications Grants; Basal Ganglia; Basic Science; Bilateral; Biology; Brain; Brain Diseases; Brain Pathology; Brain Stem; Breathing; Buffers; Carbon Monoxide; Cells; Cessation of life; Childhood; Chronic; Collection; DNA; Defect; Development; Disease; Engineering; Event; Exhibits; Foundations; Future; Genes; Genetic Heterogeneity; Genomics; Grant; Human; Hyperoxia; Hypoxia; Image; Impairment; Inborn Errors of Metabolism; Intervention; Knockout Mice; Laboratories; Lead; Leigh Disease; Longevity; Medicine; Mitochondria; Mitochondrial DNA; Mitochondrial Diseases; Modeling; Molecular; Mus; Necrosis; Necrotic Lesion; Nerve Degeneration; Nerve Regeneration; Neurites; Neurologic; Neurons; Nuclear; Orphan; Oxygen; Pathology; Patients; Pharmaceutical Preparations; Physiology; Preclinical Testing; Prevention; Proteomics; Reporting; Site; Stress; Technology; Therapeutic; Translations; Work; advanced disease; base editing; drug efficacy; efficacy testing; end stage disease; gray matter; in vivo; insight; mitochondrial dysfunction; mitochondrial genome; mouse model; natural hypothermia; nervous system disorder; neurogenesis; neuroinflammation; neuron loss; neurovascular; novel therapeutic intervention; pre-clinical; preclinical efficacy; prevent; small molecule; virtual; wasting

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.

摘要 Leigh综合征是线粒体疾病最常见的儿科表现，其特征在于： 大脑深部灰质的双侧对称性坏死病变。超过80种不同的基因- 无论是在核DNA或线粒体DNA -可以导致利综合征，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--缺氧--可以缓冲 在人类细胞、蠕虫模型和小鼠中的线粒体功能障碍。事实上，呼吸缺氧是能够充分 在Leigh综合征的Ndufs 4 KO小鼠模型中预防脑部疾病， 在患有晚期疾病的小鼠中启动，我们能够逆转神经变性。我们不 了解呼吸缺氧能够逆转疾病的全部机制，我们是否可以识别小的 分子药物，可以针对这些机制，以扭转疾病，以及是否缺氧治疗， 推广到其他线粒体脑疾病的小鼠模型。在这个应用程序中，我们将应用尖端 单细胞基因组学、蛋白质组学、mtDNA编辑和小鼠生理学研究来解决这三个问题。 挑战我们预计，这个项目可能对理解基本的 神经变性和神经再生的生物学，对治疗和 线粒体疾病患者的管理。