GENETIC CORRECTION OF RESPIRATORY CHAIN DEFICIENCIES

线粒体疾病是一类异质性疾病

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.