Mitochondrial dysfunction in pediatric disease

描述(由申请人提供)： 线粒体疾病是一组由线粒体呼吸链缺陷定义的异质性疾病。这些疾病在临床上和生化上是多样化的。线粒体功能障碍是一种相对常见的儿童疾病原因，导致多种儿科问题，包括发育迟缓、低眼压、感觉运动障碍、癫痫发作和器官衰竭。与儿童线粒体疾病相关的发病率和死亡率也很高。线粒体DNA致病突变的鉴定导致了线粒体疾病的遗传分类。许多肌肉疾病和脑疾病是由线粒体DNA编码的tRNA基因突变引起的。目前正在进行研究，以了解与这些线粒体DNA突变相关的线粒体生化变化的分子基础。虽然线粒体DNA突变的遗传鉴定有助于患者的遗传咨询，但患者的预后并不好。目前，还没有可靠的治疗方法或治疗呼吸链缺陷的方法。这项提议的目标是制定策略，纠正由于线粒体tRNA基因突变而导致的呼吸链缺陷。应该有可能通过从胞浆中导入功能性tRNA来弥补与人类线粒体tRNA基因突变相关的缺陷。其具体目标是开发一种将tRNA导入人类线粒体的系统。进口的tRNA有望弥补由于人类线粒体tRNA基因突变而导致的线粒体翻译缺陷。这项研究将作为最终治疗由编码tRNAs的线粒体DNA基因突变引起的人类脑肌病的模型。

DESCRIPTION (provided by applicant): The mitochondrial diseases are a heterogeneous group of disorders that have been defined by deficits of the Mitochondrial respiratory chain. These diseases are clinically and biochemically diverse. Mitochondrial dysfunction is a relatively common cause of disease in children, leading to a wide variety of pediatric problems, including developmental delays, hypotonia, sensorimotor impairment, seizures, and organ failure. There is also significant morbidity and mortality associated with mitochondrial diseases in children. The identification of pathogenic mutations in mitochondrial DNA has resulted in a genetic classification of mitochondrial diseases. A number of myopathies and encephalonryopathies result from mutations in mitochondrial DNA-encoded tRNA genes. Investigations are being conducted to understand the molecular basis for the biochemical alterations of mitochondria associated with these mitochondrial DNA mutations. While the genetic identification of mitochondrial DNA mutations will aid the genetic counseling of patients, the prognosis of patients is not good. Currently, there are-no reliable treatments or therapies available for respiratory chain deficiencies. The goal of this proposal is to develop strategies to correct respiratory chain deficiencies resulting from mutations in mitochondrial tRNA genes. It should be possible to complement defects associated with human mitochondrial tRNA gene mutations by importing a functional tRNA from the cytosol. The specific goal is to develop a system for the import of tRNA into human mitochondria. Imported tRNAs are expected to complement the defects in mitochondrial translation due to mutations of the human mitochondrial tRNA genes. This investigation will serve as a model for the eventual treatment of human encephalomyopathies caused by mutations in mitochondrial DNA genes encoding tRNAs.