Preventing and reversing mitochondrial Leigh syndrome with hypoxia

预防和逆转缺氧线粒体利氏综合征

基本信息

批准号：
10544012
负责人：
Vamsi Krishna Mootha
金额：
$ 53.73万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
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/10544012
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 Dedications Defect Development Disease Engineering Event Exhibits Foundations Future Genes Genetic Heterogeneity Genomics Grant Growth Human Hyperoxia Hypoxia Image Impairment Inborn Errors of Metabolism Intervention Knockout Mice Laboratories 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 improved 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

项目摘要

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.

抽象的 Leigh 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双侧对称的坏死性病变——超过 80 个不同的基因。无论是在核 DNA 还是线粒体 DNA 中——都可能是 Leigh 综合征的根源，但我们尚未批准我们最近发现低氧（缺氧）可以缓冲多种形式的疾病。人类细胞、线虫模型和小鼠线粒体功能障碍的研究事实上，呼吸缺氧是能够完全缓解的。预防 Leigh 综合征 Ndufs4 KO 小鼠模型中的脑部疾病，以及当缺氧呼吸时在患有晚期疾病的小鼠中启动，我们能够逆转神经退行性变。了解呼吸缺氧逆转疾病的完整机制，我们是否可以识别微小的可以针对这些机制来逆转疾病的分子药物，以及缺氧疗法推广到线粒体脑疾病的其他小鼠模型在本申请中，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来解决这三个问题我们预计该项目可能会对理解基本原理产生重要影响。神经变性和神经再生的生物学，对治疗和神经再生具有重要的未来影响线粒体疾病患者的管理。