Mitochondrial dysfunction in pediatric disease

描述（由申请人提供）： 线粒体疾病是由线粒体呼吸链缺陷定义的一组异质性疾病。这些疾病在临床上和生化上是多样的。线粒体功能障碍是儿童中相对常见的疾病原因，导致各种儿科问题，包括发育迟缓、张力减退、感觉运动障碍、癫痫发作和器官衰竭。在儿童中也存在与线粒体疾病相关的显著发病率和死亡率。线粒体DNA中致病性突变的鉴定导致了线粒体疾病的遗传分类。许多肌病和脑病由线粒体DNA编码的tRNA基因突变引起。正在进行调查，以了解与这些线粒体DNA突变相关的线粒体生化改变的分子基础。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，没有可靠的治疗或疗法可用于呼吸链缺陷。该提案的目标是开发策略来纠正线粒体tRNA基因突变导致的呼吸链缺陷。通过从细胞质中导入功能性tRNA，可以弥补与人类线粒体tRNA基因突变相关的缺陷。具体目标是开发一种将tRNA导入人类线粒体的系统。预期输入的tRNA将补充由于人类线粒体tRNA基因突变而导致的线粒体翻译缺陷。这项研究将作为一个模型，最终治疗人类脑肌病引起的线粒体DNA基因编码的tRNA突变。

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.