Toxic Probes of Axonopathy

申请者描述(申请人提供)：申请人打算在拟议的5年研究生涯奖励期结束时，提高他的知识和研究技能，以进行以神经科学为重点的独立科学研究。他将广泛参与神经毒理学研究，还将参加研讨会、期刊俱乐部、科学会议和教学活动。该研究计划建议使用神经毒性芳香族伽马二酮作为工具来研究巨大近端神经丝状轴索病(GPNA)的机制和生物标志物。用1，2-二乙酰苯(1，2-DAB)处理的啮齿动物在前角细胞、前根和较小范围内的背根神经节形成GPNA。前角细胞GPNA也可见于肌萎缩侧索硬化症患者的早期尸检。其目的是：A)了解伽马二酮诱导的GPNA的机制和确定生物标志物；B)增加知识和发展研究技能，以便能够独立进行神经毒理学研究。具体目的是：1)确定1，2，4-三乙酰苯(1，2，4-TRAb)和1，2，4，5-四四苯(1，2，4，5-Teab)的神经毒性性质，这两种化合物都是芳香族伽马二酮1，2-DAB的近亲；2)捕获、比较和对比与伽马二酮神经病相关的蛋白质谱和基因表达谱(如果时间允许)，以及3)确定导致GPNA发展的分子途径。这些目标将使用功能(轴突运输)、形态和组学(蛋白质组学和基因组学)方法的组合来实现。

DESCRIPTION (provided by applicant): The applicant intends to enhance his knowledge and develop research skills to conduct independent scientific neuroscience-focused research at the end of the proposed 5-year research career award period. He will be extensively involved in performing neurotoxicological research and will also participate in seminars, journals clubs, scientific meetings and teaching activities. The research plan proposes to use neurotoxic aromatic gamma-diektones as tools to study mechanisms and biomarkers of giant proximal neurofilamentous axonopathy (GPNA). Rodents treated with 1,2-diacetylbenzene (1,2-DAB) develop GPNA in anterior horn cells, ventral roots and, to a lesser extend, in the dorsal root ganglia. Anterior horn cell GPNA is also seen in early post-mortem biopsies of subjects with amyotrophic lateral sclerosis. The objectives are: A) to understand mechanisms and identify biomarkers of gamma-diketone-induced GPNA to B) enhance knowledge and develop research skills to be able to conduct neurotoxicological research independently. Specific aims are: 1) to determine neurotoxic properties of 1,2,4-triacetylbenzene (1,2,4-TrAB) and 1,2,4,5-tetracetylbenzene (1,2,4,5-TeAB), both cousins of the aromatic gamma-diketone 1,2-DAB, 2) to capture, compare and contrast protein profiles and gene expression profiles (time permitting) associated with gamma-diketone neuropathy, and 3) to identify molecular pathways that lead to the development of GPNA. These goals will be reached using a combination of functional (axonal transport), morphologic and omics (proteomics and genomics) methodologies.