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

• 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
• 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

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.

该K99/ROO应用的总体目标是过渡到独立研究者 位置，并识别和表征遗传基因座，在遗传性周围神经病中起作用。我的 长期职业目标是将自己确立为神经遗传学领域的独立研究者。 周围神经病是一组疾病，其特征是运动功能受损和感觉丧失 在四肢。大约2.4％的一般人群受周围神经病的影响，使得 这些疾病引起了重大公共卫生的关注。对所涉及的基因的更完整理解 在周围神经病中将提供对这些疾病的病因的见解，并有助于发展 更有效的疗法。两个编码酶的基因，这些酶为tRNA分子带有同源 氨基酸（ARS）与遗传的周围神经病有关。我目前的研究涉及 确定与这些基因之一（GARS）中突变相关的分子病理学。这项工作 已经揭示了大多数突变与功能丧失有关。此外，野生型 GARS与人类外周神经轴突中的颗粒相关。因此，我假设GARSASSASSASSASSASS 轴突中需要颗粒以进行局部tRNA充电，其他ARS可能在 遗传性周围神经病。为了解决这个问题，我将：（特定目标1）建立蛋白质含量和 轴突中与GARS相关的颗粒的功能； （特定目标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样品中的突变。我的另一个领域 当前的研究涉及研究Sox10基因座的转录调控，该调节编码A 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 转录调节某些通常在周围神经病患者中突变的基因。我 因此，假设Sox10在转录上调节了对周围神经健康重要的其他基因。 为了解决这个问题，我将（特定目标3）识别和表征周围神经中的Sox10-target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）有关所有ARS基因在遗传外周神经病中的作用的知识； （iii）在周围神经中由Sox10调节的更完整的基因面板。这 该奖项的培训（K99）部分将由国家人类基因组的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的公认领导者 基因组学。