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.

抽象的利综合征是线粒体疾病的最常见的儿科表现，其特征是双侧对称，大脑深灰色物质中的坏死病变。超过80种不同的基因 - 在核DNA或线粒体DNA中 - 可以是Leigh综合征的基础，但我们尚未批准这种致命疾病的药物。我们最近发现，低氧（低氧）可以缓冲多种形式人类细胞，蠕虫模型和小鼠的线粒体功能障碍。实际上，呼吸缺氧能够完全预防NDUFS4 Leigh综合征的NDUFS4 KO小鼠模型，当缺氧呼吸为在患有晚期末期疾病的小鼠中启动，我们能够逆转神经变性。我们没有了解呼吸缺氧能够逆转疾病的完整机制，我们是否可以识别小的可以针对这些机制逆转疾病的分子药物，以及缺氧治疗是否概括到其他小鼠脑疾病的小鼠模型。在此应用程序中，我们将应用最前沿单细胞基因组学，蛋白质组学，mtDNA编辑和小鼠生理学研究，以解决这三个挑战。我们预计该项目可能对理解基本神经退行性和神经变性的生物学，对治疗的未来重要意义线粒体疾病患者的管理。