Genetic and genomic approaches for studying inherited peripheral neuropathies

这个K99/Roo应用程序的首要目标是过渡到独立的调查员 定位，并识别和表征在遗传性周围神经病中起作用的遗传基因座。我的 长期的职业目标是将自己确立为神经遗传学领域的一名独立研究员。 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 在四肢上。大约2.4%的普通人群受到周围神经病变的影响，使 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 将提供对这些疾病的病因的洞察，并帮助发展 更有效的治疗方法。两个编码酶的基因，使tRNA分子与其同源物充电 氨基酸(ARs)与遗传性周围神经病变有关。我目前的研究涉及 确定与其中一个基因突变相关的分子病理学(GARS)。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)确定蛋白质含量和 GARS相关颗粒在轴突中的功能；以及(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分离的DMA样本中的突变。我的另一个领域 目前的研究包括研究Sox10基因座的转录调控，该基因座编码一种 转录因子在周围神经发育和功能中起重要作用。重要的是，Sox10 转录调控某些在周围神经病患者中常见的突变基因。我 因此，假设Sox10转录调控其他对周围神经健康重要的基因。 为了解决这一问题，我将(特定目标3)识别和表征周围神经中的Sox10靶基因 系统。完成这些具体目标将有助于：(1)更好地了解全球资源评估系统在以下方面的作用 周围神经轴突；(Ii)所有ARS基因在遗传性周围神经疾病中的作用的知识； 以及(Iii)在外周神经中受Sox10转录调控的一组更完整的基因。这个 该奖项的培训(K99)部分将由国家人类基因组研究所的Eric D.Green博士指导 研究所。格林博士是人类遗传学和比较研究领域公认的领导者。 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.