Genetic and genomic approaches for studying inherited peripheral neuropathies

此K99/ROO应用程序的总体目标是过渡到独立调查员 位置，并确定和表征遗传性周围神经病变中的作用的遗传基因座。我 我的长期职业目标是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%的普通人群受到周围神经病变的影响， 这些疾病是一个重大的公共卫生问题。更全面地了解与之相关的基因 在周围神经病变中的应用将提供对这些疾病病因的深入了解，并有助于 更有效的治疗。两个基因编码的酶，负责tRNA分子与其同源 氨基酸（ARSs）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（加尔斯）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 加尔斯与人外周神经轴突中的颗粒相关。因此，我假设GARS与 轴突中的颗粒是局部tRNA充电所必需的，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）建立蛋白质含量， GARS相关颗粒在轴突中的功能;和（具体目标2）筛选所有人类ARS基因， 从患有遗传性周围神经病变的患者分离的DMA样品中的突变。我的另一个领域 目前的研究包括研究SOX 10基因座的转录调控，该基因座编码一种 在外周神经发育和功能中具有重要作用的转录因子。重要的是，SOX 10 转录调节某些基因，这些基因通常在周围神经病变患者中突变。我 因此，假设SOX 10转录调节其他基因的重要外周神经健康。 为了解决这个问题，我将（具体目标3）确定和表征周围神经系统中的SOX 10靶基因。 系统完成这些具体目标将提供：（i）更好地理解加尔斯在以下方面的作用： 周围神经轴突;（ii）关于所有ARS基因在遗传性周围神经病中的作用的知识; 和（iii）外周神经中由SOX 10转录调节的一组更完整的基因。的 培训（K99）部分，这个奖项将指导博士埃里克D。国家人类基因组的绿色 研究院绿色博士是人类遗传学和比较遗传学领域公认的领导者。 基因组学

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.