权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Exploring the functions of tRNA synthetases in the nucleus and their relationship to CMT

探索细胞核中 tRNA 合成酶的功能及其与 CMT 的关系

基本信息

批准号：
10227442
负责人：
Robert W Burgess
金额：
$ 9.43万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10227442
关键词：
Affect Alleles Alzheimer&apos s Disease Amino Acids Amino Acyl-tRNA Synthetases Aminoacylation Amyotrophic Lateral Sclerosis Biological Biological Models Biological Process Blood Vessels Body Weight Cell Nucleus Charcot-Marie-Tooth Disease Chromosomes Data Deformity Development Disease Distal Drosophila genus Engineering Enzymes Eukaryotic Cell Gene Family Genetic Transcription Goals HDAC1 gene Hereditary Motor and Sensory Neuropathies Heterozygote Hindlimb Homozygote Huntington Disease Inflammation Inherited Knock-in Knowledge Lead Length Limb structure Link Modeling Mus Muscle Mutation Nerve Degeneration Neurodegenerative Disorders Neurons Neuropathy Nuclear Nuclear Translocation Oxidative Stress Parkinson Disease Pathway interactions Patients Peripheral Nerves Peripheral Nervous System Diseases Phenotype Physiological Prevalence Process Protein Biosynthesis Reaction Reagent Regulator Genes Role Sensory Specificity System Tissues Transfer RNA Transfer RNA Aminoacylation United States Weight maintenance regimen YARS gene biological adaptation to stress gain of function in vivo in vivo Model motor impairment mouse model multiple omics mutant nervous system disorder novel skeletal wasting

项目摘要

Abstract Charcot-Marie-Tooth (CMT) disease, also known as hereditary motor and sensory neuropathy (HMSN), is the most common form of inherited peripheral neuropathy, with an estimated prevalence of 1 in 2500 people, equating to approximately 125,000 people in the United States. CMT affects peripheral nerves in a length- dependent manner and is characterized by weakness and wasting of the distal limb muscles leading to progressive motor impairment, sensory loss, and skeletal deformities. No therapy is available for CMT patients. The largest gene family implicated in CMT encodes aminoacyl-tRNA synthetases (aaRSs), which are essential enzymes that catalyze the first reaction in protein biosynthesis, namely, the charging of transfer RNAs (tRNAs) with their cognate amino acids. However, understanding the connection between CMT and aaRSs is a challenge. Because aaRSs are essential players in protein synthesis, it is believed that the CMT-causing mutations in tRNA synthetases must affect protein synthesis in some way. Curiously, 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 inheritance, 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 aaRSs in CMT disease. Intriguingly, cytosolic aaRSs are also detected in the nucleus of eukaryotic cells. While the initial hypothesis was that aaRSs function here in proofreading newly-synthesized tRNAs, later findings suggest that the nuclear-localized aaRSs are involved in regulating a wide range of biological processes including vascular development, inflammation, and stress responses mainly due to their distinctive abilities to interact with the transcriptional machinery. However, the biological function of nuclear TyrRS has never been investigated in vivo in a mammalian system. The goal of this project is to explore the physiological functions of aaRSs in the nucleus and their relationship to CMT. Our main focus is on TyrRS, because of the established reagents and knowledge necessary for exploration in a mammalian system and because of the recent evidence from a Drosophila model for the involvement of nuclear TyrRS in CMT. Although the main focus is on TyrRS, we will probe commonality with other subtypes of peripheral neuropathy as well as other neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. This is because the nuclear function of TyrRS is likely to be generally related to oxidative stress and to other important pathways and gene regulators that are relevant to the neurodegenerative process independent of CMT mutations.

摘要