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Deciphering the role of amino acid transporters in mitochondrial myopathy

破译氨基酸转运蛋白在线粒体肌病中的作用

基本信息

批准号：
9788032
负责人：
Prashant Mishra
金额：
$ 35.64万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-20 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9788032
关键词：
Affect Alleles Amino Acid Transporter Amino Acids Animal Diseases Animals Carbon Carbon Isotopes Catabolism Cell membrane Cells Complement Cultured Cells Defect Deletion Mutation Diet Disease Disease Progression Engineering Excision Family Family member Functional disorder Glucose Glutamates Glutamine Goals Health Homeostasis Impairment Individual Investigation Isotopes Knock-out Lead Metabolic Metabolic Pathway Metabolism Mitochondria Mitochondrial DNA Mitochondrial Diseases Mitochondrial Myopathies Molecular Motor Mus Muscle Muscle function Mutation Myopathy Nutrient Organelles Outcome Oxidative Phosphorylation Pathogenicity Pathology Pathway interactions Patients Pharmaceutical Preparations Pharmacology Physiology Plasma Role Route Secondary to Severities Skeletal Muscle Stable Isotope Labeling System Techniques Testing Tissues Up-Regulation Work amino acid metabolism body system design glucose metabolism human disease improved in vivo member mitochondrial DNA mutation mitochondrial dysfunction mitochondrial genome mitochondrial metabolism mouse model muscle physiology muscular system mutant new therapeutic target novel novel therapeutics outcome forecast oxidation response skeletal disorder skeletal muscle metabolism solute targeted treatment therapy development

项目摘要

Project Summary Mitochondria are centrally involved in the conversion of nutrients into energy, and thus, damage to this organelle results in altered nutrient catabolism. The skeletal muscle system is prominently affected in the setting of mitochondrial dysfunction, but little is known regarding the activity of metabolic pathways in diseased muscular tissue. Our preliminary work has discovered that central carbon metabolism is altered in cultured cells with pathogenic mitochondrial genome (mtDNA) mutations, and identified alterations in key members of the solute transport carrier (SLC) family which regulate these perturbations. Importantly, similar alterations in SLC family members, particularly the xc- transport system, occur in muscular tissues of subjects with mitochondrial myopathy. Using mouse models of mitochondrial disease, we propose three specific aims to characterize the role of xc- in altering metabolic fluxes in diseased skeletal muscle. In Aim 1, we will characterize metabolic pathways in diseased animals using stable isotope labeling techniques. These results will quantitate in vivo metabolism in mutant muscle tissue, providing a detailed mapping of the differences between normal and diseased states. In Aim 2, we will investigate the role of xc- in regulating skeletal muscle metabolism, making use of an available knockout allele. In Aim 3, we will test the hypothesis that altering xc- activity modulates disease progression in diseased mice, by following muscular physiology and function in live animals. Together, these aims will quantitate metabolic alterations in mitochondrial myopathies, and relate them to in vivo muscle function and health. The results have the potential to identify new therapies targeting carbon metabolism which may be beneficial for patients suffering from mitochondrial myopathies.

项目总结