Mitochondrial dysfunction in pediatric disease

儿科疾病中的线粒体功能障碍

• 批准号: 6754543
• 负责人: MICHAEL P KING
• 金额: $ 19.63万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6754543
• 关键词: DNA directed RNA polymerase; aminoacid tRNA ligase; cell line; central nervous system disorders; child (0-11); gene expression; gene mutation; genetic translation; immunocytochemistry; lysine; mitochondrial disease /disorder; model design /development; pediatrics; transfection; transfer RNA; western blottings; yeasts

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.

描述（由申请人提供）： 线粒体疾病是一种由线粒体呼吸链缺陷定义的异质性疾病。这些疾病在临床和生化上是多种多样的。线粒体功能障碍是儿童疾病的相对常见原因，导致各种各样的小儿问题，包括发育延迟，肌张力低下，感觉运动障碍，癫痫发作和器官衰竭。儿童的线粒体疾病也存在明显的发病率和死亡率。线粒体DNA中致病突变的鉴定导致了线粒体疾病的遗传分类。线粒体DNA编码的tRNA基因的突变引起的许多肌病和脑病。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改变的分子基础。线粒体DNA突变的遗传鉴定将有助于患者的遗传咨询，但患者的预后不好。当前，没有可靠的治疗方法或疗法可用于呼吸链缺陷。该提案的目的是制定策略，以纠正线粒体tRNA基因突变引起的呼吸链缺陷。应该通过从细胞质中导入功能性tRNA来补充与人线粒体tRNA基因突变相关的缺陷。具体的目标是开发将tRNA导入人线粒体的系统。由于人线粒体TRNA基因的突变，导入的TRNA有望补充线粒体翻译中的缺陷。这项研究将成为最终治疗由编码TRNA的线粒体DNA基因突变引起的人类脑膜病的模型。