Toxic Probes of Axonopathy

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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.