Molecular prostheses for mitochondrial disorders

用于线粒体疾病的分子假体

基本信息

批准号：
8180714
负责人：
Vamsi Krishna Mootha
金额：
$ 110.89万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-30 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8180714
关键词：
ATP Synthesis Pathway Address Bacterial Genome Biochemical Biochemical Pathway Bioinformatics Biological Factors Biology Boxing Breathing Bypass Cell model Cells Cessation of life Chemicals Childhood Collection Complex Defect Diabetes Mellitus Diagnosis Disease Electron Transport Evolution Foundations Functional disorder Generic Drugs Genes Genomics Hereditary Disease Heterogeneity Human Inborn Errors of Metabolism Individual Inherited Interruption Laboratories Libraries Live Birth Macromolecular Complexes Medical Metabolic Methods Microbe Mitochondria Mitochondrial Diseases Mitochondrial Respiratory Chain Deficiencies Molecular Mutate NADH Natural regeneration Nature Nerve Degeneration Organ failure Organism Oxidation-Reduction Oxygen Pathology Patients Prevalence Prosthesis Proteins Protozoa Respiratory Chain Saccharomyces cerevisiae Scanning Series Therapeutic Work Yeasts bacterial genetics base cofactor disease phenotype emerging adult enzyme replacement therapy fungus human disease infancy innovation microbial microorganism mitochondrial dysfunction neglect novel therapeutic intervention novel therapeutics polypeptide respiratory small molecule young adult

项目摘要

DESCRIPTION (provided by applicant): Genetic disorders of the mitochondrion represent the most common collection of inborn errors of metabolism, impacting over 1:4000 live births. They are characterized by an inherited defect in the respiratory chain, whose blockade leads to multisystem organ failure and inevitable death. Although there has been tremendous progress in elucidating the molecular bases of these disorders, with over 100 disease genes identified to date, not a single therapy has been proven to be useful. Because so many different genes can be mutated in these disorders, traditional enzyme replacement therapy is unlikely to be a useful approach. We propose a potentially generic therapeutic strategy that that aims to target the common biochemical pathway that is altered in mitochondrial disorders. Our approach is inspired by nature: a number of microbes, protozoa, and fungi have evolved relatively simple biochemical innovations that allow them to survive without respiratory chains. We propose to use computational genomics to systematically scan the thousands of sequenced bacterial genomes to identify those lacking complete respiratory chains, and then to use a mix of bioinformatics, bacterial genetics, and chemical biology to systematically identify the proteins and small molecules that endow them an ability to survive without a complete respiratory chain. We will create a library of such polypeptides and natural products and evaluate their ability to alleviate pathology in human cellular models of mitochondrial disease. If successful, this project will yield an entire pipeline of small molecules and proteins that may represent the starting point for a new class of therapeutics for these disorders. PUBLIC HEALTH RELEVANCE: The mitochondrial respiratory chain disorders collectively represent the most common inborn error of metabolism. The prevalence is estimated to be 1:4000 live births. These disorders can present in childhood or in young adulthood and are difficult to diagnose and manage. At present there is not a single proven therapy. The proposed project aims to develop a new therapeutic approach to these disorders.

描述（由申请人提供）：线粒体的遗传疾病代表了新陈代谢的最常见的先天错误收集，影响了1：4000个活产。它们的特征是呼吸链中的遗传缺陷，其封锁导致多系统器官衰竭和不可避免的死亡。尽管在阐明这些疾病的分子碱基碱基方面取得了巨大进展，但迄今为止确定了100多种疾病基因，但事实证明，没有一种疗法有用。由于可以在这些疾病中突变许多不同的基因，因此传统的酶替代疗法不太可能是一种有用的方法。我们提出了一种潜在的通用治疗策略，该策略旨在针对线粒体疾病改变的常见生化途径。我们的方法受自然的启发：许多微生物，原生动物和真菌已经进化出相对简单的生化创新，使它们能够在没有呼吸链的情况下生存。我们建议使用计算基因组学来系统地扫描成千上万的测序细菌基因组，以鉴定缺乏完全呼吸链的人，然后使用生物信息学，细菌遗传学和化学生物学的混合物系统地识别蛋白质和小分子，使它们能够在没有完整呼吸链的情况下生存它们。我们将创建此类多肽和天然产品的库，并评估它们在线粒体疾病的人类细胞模型中减轻病理学的能力。如果成功的话，该项目将产生整个小分子和蛋白质的管道，这可能代表了这些疾病的新疗法的起点。公共卫生相关性：线粒体呼吸链疾病统称是最常见的新陈代谢错误。患病率估计为1：4000个活产。这些疾病可以在童年或成年期间出现，并且难以诊断和管理。目前没有一种经过验证的疗法。拟议的项目旨在为这些疾病开发一种新的治疗方法。