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

• 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
• 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

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.

抽象的 charcot-marie-tooth（CMT）疾病是遗传的最常见形式 周围神经病，影响大约有2500人中的1人 美国约有125,000人。没有有效的CMT疗法 目前存在。这些疾病特别影响周围神经系统，是 以进行性运动神经元变性，肌肉萎缩和感觉为特征 损失。神经遗传学研究的最新进展已经发现了氨基酰基-TRNA 合成酶是与CMT有关的最大基因家族。其中，Gars，编码 糖基-TRNA合成酶（Glyrs）是第一个鉴定的成员，其突变 引起CMT（CMT2D）的主要轴突形式。尽管有广泛的要求 用于所有细胞中蛋白质生物合成的Glyrs，该基因的突变引起选择性 周围轴突的变性导致远端运动功能缺陷。 该项目的目的是确定CMT2D引起疾病的机制。我们的 中心假设是CMT2D引起的突变体Glyrs获得异常结合 直接拮抗运动神经元基本信号通路的活性 生存期，突变类药物的毒性功能可能与失调的失调有关 野生型Glyrs的翻译功能。我们的假设是基于我们的结果 从这笔赠款的上一个资金期开始，以及我们与其他资助的合作 实验室。通过从氢 - 偏见交换的广泛方法 分析，X射线晶体学，生化和基于细胞的分析对小鼠研究， 该项目不仅会阐明CMT2D，从而导致机制和开门的门 为CMT2D患者制定治疗策略，但也揭示了重要的 Glyrswt的调节功能超出其经典酶功能在蛋白质中 合成。