GENETIC CORRECTION OF RESPIRATORY CHAIN DEFICIENCIES

线粒体疾病是一组不同种类的疾病， 是由肌肉中特定的形态变化定义的，并由 线粒体呼吸链的缺陷。形态上的 这些疾病的特征包括不整的红色纤维(广泛的 肌肉纤维中线粒体的增殖)，以及异常 线粒体中的准晶包裹体和膜结构。这些 疾病在临床上和生化上是多样化的。而遗传基因 线粒体突变的鉴定将有助于遗传咨询 在患者中，患者的预后不佳。目前，有以下几种 呼吸链尚无可靠的治疗方法或疗法 不足之处。一旦知道了具体的缺陷及其原因，它将 有可能开发出合理的治疗方法来治疗患有 这些疾病目前是无法治愈的，而且往往是致命的。 这项提议的目标是继续对表型的分析 以及几种特定mRDNA突变的分子遗传学后果 导致心肌病和神经肌肉疾病，并 研究治疗线粒体疾病的遗传疗法， 这些线粒体DNA突变导致呼吸链缺陷。 具体地说，这项提议的目的是研究分子 线粒体tRNA亮氨酸(UUR)突变的遗传机制 基因导致蛋白质合成、呼吸链活性、 和细胞生长。随着发病机制的阐明， 缓解这些缺陷的特定遗传疗法将是 调查过了。此外，将进行研究，以确定是否 线粒体DNA编码蛋白中的突变可以由修改后的 专为核表达和定位于线粒体而设计的基因。 这些研究将作为两种疾病最终治疗的模式 导致人类疾病的线粒体DNA突变的主要类别，突变 线粒体tRNA和蛋白质编码基因。

The mitochondrial diseases are a heterogeneous group of disorders which have been defined by specific morphological alterations in muscle, and by deficits of the mitochondrial respiratory chain. The morphological hallmarks of these diseases include ragged-red fibers (an extensive proliferation of mitochondria in muscle fibers), and abnormal paracrystalline inclusions and membrane structures in mitochondria. These diseases are clinically and biochemically diverse. While the genetic identification of mitochondrial 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. Once specific defects and their causes are known, it will be possible to develop rational therapies for patients suffering from these currently incurable, and often fatal diseases. The goal of this proposal is to continue the analysis of the phenotypic and molecular genetic consequences of several specific mRDNA mutations resulting in cardiomyopathies and neuromuscular disorders and to investigate genetic therapies for the treatment of mitochondrial, respiratory chain deficiencies caused by these mtDNA mutations. Specifically, the aim of this proposal is to investigate the molecular genetic mechanisms by which mutations in the mitochondrial tRNA Leu(UUR) gene cause deficiencies in protein synthesis, respiratory chain activity, and cell growth. As the mechanisms of pathogenesis are elucidated, specific genetic therapies to mitigate these deficiencies will be investigated. Furthermore, studies will be conducted to determine whether a mutation in a mtDNA-encoded protein can be complemented by a modified gene designed for nuclear expression and targeting to the mitochondria. These studies will serve as models for the eventual treatment of two of the major classes of mTDNA mutations resulting in human disease, mutations of mitochondrial tRNA and protein encoding genes.