Molecular prostheses for mitochondrial disorders

描述（由申请人提供）：先天性代谢缺陷的遗传性疾病是最常见的先天性代谢缺陷，影响超过1：4000的活产婴儿。它们的特点是呼吸链的遗传缺陷，呼吸链的阻断导致多系统器官衰竭和不可避免的死亡。虽然在阐明这些疾病的分子基础方面取得了巨大进展，迄今已确定了100多个疾病基因，但没有一种治疗方法被证明是有用的。由于在这些疾病中有如此多的不同基因可以突变，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，旨在靶向线粒体疾病中改变的常见生化途径。我们的方法受到自然界的启发：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数千个测序的细菌基因组，以识别那些缺乏完整呼吸链的细菌，然后使用生物信息学，细菌遗传学和化学生物学的组合来系统地识别赋予它们在没有完整呼吸链的情况下生存能力的蛋白质和小分子。我们将创建这样的多肽和天然产物的库，并评估它们在线粒体疾病的人类细胞模型中减轻病理的能力。如果成功，该项目将产生一个完整的小分子和蛋白质管道，可能代表这些疾病的一类新疗法的起点。 公共卫生相关性：线粒体呼吸链疾病共同代表了最常见的先天性代谢缺陷。估计发病率为1：4000活产。这些疾病可以出现在儿童时期或青年时期，并且难以诊断和管理。目前还没有一种单一的经证实的疗法。拟议的项目旨在为这些疾病开发一种新的治疗方法。

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.