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Developmental mechanisms of CNS pathology in mitochondrial disease

线粒体疾病中枢神经系统病理学的发育机制

基本信息

批准号：
10468301
负责人：
Simon C Johnson
金额：
$ 47.13万
依托单位：
SEATTLE CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-15 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10468301
关键词：
Affect Age Attenuated Birth Caenorhabditis elegans Cardiovascular Diseases Childhood Clinical Complex Data Defect Development Developmental Biology Disease Electron Transport Environmental Exposure Etiology Event FRAP1 gene Functional disorder Genetic Goals Growth Health Homologous Gene Human Human Pathology Hypoxia Individual Intervention Knockout Mice Lead Leigh Disease Life Link Mediating Metabolic Metabolic Diseases Metabolic dysfunction Mitochondria Mitochondrial Diseases Modeling Molecular Mutation Nematoda Neurodegenerative Disorders Neurologic Neurologic Symptoms Onset of illness Organ Pathogenesis Pathology Pathway interactions Phenotype Physiological Role Seizures Sirolimus Specificity Symptoms Syndrome Testing Treatment Efficacy Work acute symptom age related associated symptom attenuation base experimental study gene product human model in utero insight ketogenic diet mTOR Inhibitor mTOR inhibition mitochondrial dysfunction mouse model neurodevelopment novel postnatal postnatal development postnatal period preclinical study prevent therapy development trait

项目摘要

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.

项目总结/文摘

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The immune system as a driver of mitochondrial disease pathogenesis: a review of evidence.

DOI：
10.1186/s13023-022-02495-3
发表时间：
2022-09-02
期刊：
Orphanet journal of rare diseases
影响因子：
3.7
作者：
通讯作者：

Peripheral macrophages drive CNS disease in the Ndufs4(-/-) model of Leigh syndrome.

DOI：
10.1111/bpa.13192
发表时间：
2023-11
期刊：
Brain pathology (Zurich, Switzerland)
影响因子：
0
作者：
通讯作者：

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Simon C Johnson其他文献

Evaluating the efficacy of vatiquinone in preclinical models of mitochondrial disease

评估万替醌在线粒体疾病临床前模型中的功效

DOI：
发表时间：
2024
期刊：
Research Square
影响因子：
0
作者：
Ernst;Yihan Chen;Michael Mulholland;Vivian Truong;K. James;Allison Hanaford;Simon C Johnson
通讯作者：
Simon C Johnson