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：
7680906
负责人：
Anthony Antonellis
金额：
$ 24.74万
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/7680906
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 Genome 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 Localized Location Mammals Mass Spectrum Analysis Mentors Microscopy Morbidity - disease rate Motor Mutate Mutation Myelin P0 Protein Myelin Sheath New Avenues for the Development of Therapeutics Numbers 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 Institute Research Personnel Role Sampling Schwann Cells Screening procedure Sensory Structure Time Training Transcriptional Regulation Transfer RNA Aminoacylation Translations Tyrosine-tRNA Ligase United States National Institutes of Health Variant Work YARS gene Zebrafish career comparative connexin 32 direct patient care experience in vivo insight loss of function molecular pathology neurogenetics programs research study retinal rods 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.

此 K99/ROO 申请的总体目标是过渡为独立调查员位置，并识别和表征在遗传性周围神经病中起作用的遗传位点。我的长期职业目标是使自己成为神经遗传学领域的独立研究者。周围神经病是一组以运动功能受损和感觉丧失为特征的疾病在四肢。大约 2.4% 的普通人群患有周围神经病变，这使得这些疾病是一个重大的公共卫生问题。对所涉及的基因有更全面的了解周围神经病的研究将提供对这些疾病的病因学的深入了解，并有助于发展更有效的治疗方法。两个编码酶的基因将同源的 tRNA 分子带入氨基酸（ARS）与遗传性周围神经病有关。我目前的研究涉及确定与这些基因之一（GARS）突变相关的分子病理学。这部作品研究表明，大多数突变与功能丧失有关。此外，野生型 GARS 与人类周围神经轴突中的颗粒相关。因此我假设 GARS 相关轴突中需要颗粒来进行局部 tRNA 充电，而其他 ARS 可能在其中发挥作用遗传性周围神经病。为了解决这个问题，我将：（具体目标 1）确定蛋白质含量和轴突中 GARS 相关颗粒的功能；（具体目标 2）筛选所有人类 ARS 基因从遗传性周围神经病患者中分离出的 DMA 样本中存在突变。我的另一个领域目前的研究涉及 SOX10 位点的转录调控，该位点编码转录因子在周围神经发育和功能中具有重要作用。重要的是，SOX10 转录调节周围神经病患者中常见突变的某些基因。我因此推测 SOX10 转录调节对周围神经健康重要的其他基因。为了解决这个问题，我将（具体目标 3）识别并表征周围神经中的 SOX10 靶基因系统。完成这些具体目标将提供：(i) 更好地理解 GARS 在周围神经轴突； (ii) 了解所有 ARS 基因在遗传性周围神经病中的作用； (iii) 周围神经中由 SOX10 转录调节的更完整的基因组。这该奖项的培训（K99）部分将由国家人类基因组中心的 Eric D. Green 博士指导研究所。格林博士是人类遗传学和比较领域公认的领导者基因组学。