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Extra-translational roles of aminoacyl tRNA synthetases in connection to disease

氨酰 tRNA 合成酶与疾病相关的翻译外作用

基本信息

批准号：
9177065
负责人：
Xiang-Lei Yang
金额：
$ 49.69万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-06 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9177065
关键词：
Address Adverse effects Affect Amino Acyl-tRNA Synthetases Animals Area Axon Binding Binding Sites Biochemical Biological Assay Cells Charcot-Marie-Tooth Disease Collaborations Defect Deuterium Development Diagnostic Disease Distal Exhibits Funding Future GARS gene Gene Family Genes Genetic Genetically Engineered Mouse Goals Grant Human Hydrogen In Vitro Inherited Knock-out Knockout Mice Laboratories Lead Ligands Light Link Medical Membrane Proteins Methods Molecular Molecular Conformation Motor Motor Neurons Mus Muscular Atrophy Mutagenesis Mutation Nature Neonatal Neuropathy Neuropilin-1 Pathway interactions Patients Peripheral Peripheral Nervous System Peripheral Nervous System Diseases Phenotype Physiological Play Protein Biosynthesis Role Sensory Signal Pathway Symptoms Testing Therapeutic United States Vascular Endothelial Growth Factors X-Ray Crystallography abstracting base effective therapy extracellular gain of function in vivo loss of function member motor function improvement motor neuron degeneration mouse model mutant neurogenetics overexpression prevent receptor small molecule tool

项目摘要

Abstract Charcot-Marie-Tooth (CMT) diseases are the most common form of hereditary peripheral neuropathies, affecting approximately 1 in 2,500 people equating to approximately 125,000 people in the United States. No effective therapy for CMT currently exists. The diseases specifically affect the peripheral nervous system and are characterized by progressive motor neuron degeneration, muscle atrophy, and sensory loss. Recent progress in neurogenetic studies has uncovered aminoacyl-tRNA synthetase as the largest gene family implicated in CMT. Among them, GARS, encoding glycyl-tRNA synthetase (GlyRS), is the first member identified and whose mutations cause a dominant axonal form of CMT (CMT2D). Despite the broad requirement of GlyRS for protein biosynthesis in all cells, mutations in this gene cause a selective degeneration of peripheral axons leading to deficits in distal motor function. The goal of this project is to determine the disease-causing mechanism for CMT2D. Our central hypothesis is that CMT2D-causing mutant GlyRS acquires an aberrant binding activity that directly antagonizes an essential signaling pathway for motor neuron survival, and that the toxic function of mutant GlyRS may be linked to a dysregulated, extra-translational function of wild-type GlyRS. Our hypothesis is based on our results from the previous funding period of this grant and from our collaborations with other laboratories. Through a broad range of methods from hydrogen-deuterium exchange analysis, X-ray crystallography, biochemical, and cell-based analysis to mice studies, this project will not only shed light on CMT2D causing mechanisms and open doors for developing therapeutic strategies for CMT2D patients, but also reveal important regulatory functions of GlyRSWT beyond its classic enzymatic function in protein synthesis.

摘要