Elucidating pathological mechanism of DI-CMTC

阐明DI-CMTC的病理机制

基本信息

批准号：
8611763
负责人：
Xiang-Lei Yang
金额：
$ 45.58万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8611763
关键词：
Acetylation Affect Alzheimer&apos s Disease Amino Acyl-tRNA Synthetases Aminoacylation Amyotrophic Lateral Sclerosis Animal Model Biochemistry Biological Cell Nucleus Cellular biology Charcot-Marie-Tooth Disease Collaborations Cytoplasm DNA DNA Damage Data Deformity Development Disease Drosophila genus E2F1 gene Enzymes Etiology Exclusion Family Gene Expression Profiling Gene Family Gene Targeting Genes Genetic Goals HDAC1 gene Hereditary Disease Histocompatibility Testing Inborn Genetic Diseases Inherited International Laboratories Lead Lesion Light Link Methods Modeling Molecular Biology Motor Muscular Atrophy Mutation Nerve Degeneration Neurodegenerative Disorders Neurons Nuclear Nuclear Localization Signal Oxidative Stress Parkinson Disease Pathology Pathway interactions Performance Peripheral Nerves Phenotype Process Protein Biosynthesis Proteins Publishing RNA-Binding Proteins Role Sensory Site Specificity System Testing Tissues Toxic effect Tyrosine United States Universities YARS gene autosomal dominant trait base bone loss cell injury effective therapy gain of function in vivo motor neuron degeneration mutant nervous system disorder novel public health relevance response therapeutic development transcription factor

项目摘要

DESCRIPTION (provided by applicant): Charcot-Marie-Tooth (CMT) disease is a group of inherited disorders that specifically affect the peripheral nerves system and is characterized by progressive muscle atrophy, sensory loss and bone deformities. This genetic disease, for which there is no effective therapy, is one of the most commonly inherited neurological disorders affecting approximately 1 in 2,500 people equating to approximately 125,000 people in the United States. Multiple mutations in four different aminoacyl-tRNA synthetase genes are causally linked to CMT. Thus tRNA synthetases are one of the largest gene families associated with CMT. This underscores the importance of tRNA synthetase in the etiology of the disease. Understanding the connection between CMT and tRNA synthetases is a challenge. Because tRNA synthetases are essential players in protein synthesis, the dogma has been that the CMT-causing mutations in tRNA synthetases must affect protein synthesis in some way. Intriguingly, CMT-causing mutations do not necessarily affect the aminoacylation function of the enzyme; and almost all tRNA synthetase mutations that are CMT-associated have autosomal dominant trait, suggesting a gain-of-function disease mechanism. Lastly, as protein synthesis is essential for all tissue types, the extreme tissue specificity associated with the CMT phenotypes has complicated the biological understanding of the role of tRNA synthetases in CMT disease. The goal of this project is to determine the disease-causing mechanism for DI-CMTC, a subtype of CMT caused by dominant mutations in tyrosine tRNA synthetase (TyrRS or YARS). Through international collaborations and a cross-disciplinary approach that combines methods of Drosophila genetics, biochemistry and cell and molecular biology, we will define the mechanism through which YARS mutations are linked to DI-CMTC. Broadly speaking, the tRNA synthetase family represents one class of DNA/RNA binding proteins that, as a whole, have emerged as an important player in neurodegenerative processes and as potential targets for therapeutic development. Thus, the mechanistic understanding we will obtain from the current study would certainly shed light on the etiology of other neurological disorders beyond CMT.

描述（由申请人提供）：腓骨肌萎缩症（CMT）是一组专门影响周围神经系统的遗传性疾病，其特征是进行性肌肉萎缩、感觉丧失和骨骼畸形。这种遗传病尚无有效的治疗方法，是最常见的遗传性神经系统疾病之一，影响约 2,500 人中的 1 人，相当于美国约 125,000 人。四种不同氨酰基-tRNA 合成酶基因的多个突变与 CMT 存在因果关系。因此，tRNA 合成酶是与 CMT 相关的最大基因家族之一。这强调了 tRNA 合成酶在疾病病因学中的重要性。了解 CMT 和 tRNA 合成酶之间的联系是一个挑战。由于 tRNA 合成酶在蛋白质合成中发挥重要作用，因此人们普遍认为，tRNA 合成酶中引起 CMT 的突变必定会以某种方式影响蛋白质合成。有趣的是，引起 CMT 的突变并不一定会影响该酶的氨酰化功能；几乎所有与 CMT 相关的 tRNA 合成酶突变都具有常染色体显性特征，表明功能获得性疾病机制。最后，由于蛋白质合成对于所有组织类型都至关重要，因此与 CMT 表型相关的极端组织特异性使得对 tRNA 合成酶在 CMT 疾病中作用的生物学理解变得复杂。该项目的目标是确定 DI-CMTC 的致病机制，DI-CMTC 是由酪氨酸 tRNA 合成酶（TyrRS 或 YARS）显性突变引起的 CMT 亚型。通过国际合作和结合果蝇遗传学、生物化学以及细胞和分子生物学方法的跨学科方法，我们将确定 YARS 突变与 DI-CMTC 关联的机制。从广义上讲，tRNA 合成酶家族代表了一类 DNA/RNA 结合蛋白，作为一个整体，它们已成为神经退行性过程中的重要参与者，并成为治疗开发的潜在靶标。因此，我们将从当前的研究中获得的机制理解肯定会揭示 CMT 之外的其他神经系统疾病的病因学。