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Genetic and genomic approaches for studying inherited peripheral neuropathies

研究遗传性周围神经病的遗传和基因组方法

基本信息

批准号：
7688543
负责人：
Anthony Antonellis
金额：
$ 24.34万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-16 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7688543
关键词：
Address Affect Amino Acids Amino Acyl-tRNA Synthetases Amputation Area Award Axon Binding Binding Sites Boxing Candidate Disease Gene Cells Charcot-Marie-Tooth Disease Chickens Chromosome Mapping Code Collaborations Consensus Sequence Cytoplasmic Granules Data Defect Development Diagnosis Disease Distal Distal Spinal Muscular Atrophy Enhancers Enzymes Etiology Family Fluorescence Microscopy Gene Mutation Gene Targeting General Population Genes Genetic Genetic Variation Genomics Glycine Glycine-Specific tRNA Glycine-tRNA Ligase Goals Head Health Human Human Genetics Human Genome Human Subject Research Immunoprecipitation Impairment In Vitro Inherited Knowledge Lead Limb structure Location Mammals Mass Spectrum Analysis Mentors Microscopy Morbidity - disease rate Motor Mutate Mutation Myelin P0 Protein Myelin Sheath National Human Genome Research Institute Older Population Pathogenesis Patients Pattern Peripheral Nerves Peripheral Nervous System Peripheral Nervous System Diseases Phenotype Play Positioning Attribute Property Protein Biosynthesis Proteins Public Health Research Research Ethics Committees Research Personnel Role Sampling Schwann Cells Screening procedure Sensory Structure Time Training Transcriptional Regulation Transfer RNA Aminoacylation Translations United States National Institutes of Health Variant Work YARS gene Zebrafish career comparative connexin 32 direct patient care effective therapy experience genome wide association study in vivo insight loss of function molecular pathology neurogenetics programs research study retinal rods therapeutic development transcription factor

项目摘要

The overarching objectives of this K99/ROO application are to transition to an independent investigator position, and to identify and characterize genetic loci with a role in inherited peripheral neuropathies. My long-term career goal is to establish myself as an independent investigator in the field of neurogenetics. Peripheral neuropathies are a group of diseases characterized by impaired motor function and sensory loss in the extremities. About 2.4% of the general population is affected with a peripheral neuropathy, making these diseases a significant public health concern. A more complete understanding of the genes implicated in peripheral neuropathies will provide insight into the etiology of these diseases and aid the development of more efficient therapies. Two genes encoding enzymes that charge tRNA molecules with their cognate amino acids (ARSs) have been implicated in inherited peripheral neuropathies. My current research involves determining the molecular pathology associated with mutations in one of these genes (GARS). This work has revealed that the majority of mutations are associated with a loss of function. Furthermore, wild-type GARS becomes associated with granules in human peripheral nerve axons. I thus hypothesize that GARSassociated granules are required in axons for local tRNA charging, and that other ARSs likely play a role in inherited peripheral neuropathies. To address this I will: (Specific Aim 1) establish the protein-content and function of GARS-associated granules in axons; and (Specific Aim 2) screen all human ARS genes for mutations in DMA samples isolated from patients with inherited peripheral neuropathy. Another area of my current research involves studying the transcriptional regulation of the SOX10 locus, which encodes a transcription factor with an important role in peripheral nerve development and function. Importantly, SOX10 transcriptionally regulates certain genes that are commonly mutated in patients with peripheral neuropathy. I thus hypothesize that SOX10 transcriptionally regulates other genes important for peripheral nerve health. To address this I will (Specific Aim 3) identify and characterize SOX10-target genes in the peripheral nervous system. Completing these Specific Aims will provide: (i) a better understanding of the role of GARS in peripheral nerve axons; (ii) knowledge about the role of all ARS genes in inherited peripheral neuropathies; and (iii) a more complete panel of genes transcriptionally regulated by SOX10 in peripheral nerves. The training (K99) portion of this award will be mentored by Dr. Eric D. Green at the National Human Genome Research Institute. Dr. Green is a recognized leader in the fields of human genetics and comparative genomics.

这个K99/ROO申请的首要目标是过渡到一个独立的调查员