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Targeting tubulin acetylation in spiral ganglion neurons for the treatment of hearing loss
Based on our previous studies demonstrating the role of tubulin acetylation in axonal stability and regeneration, we hypothesize that stabilizing MTs by promoting α-tubulin acetylation in SGNs will increase axonal transport of mitochondria and other cargoes such as mRNAs, enhancing survival and regeneration of axons exposed to excitotoxic insult, and thus protect against deafness.
In the proposed Specific Aims, we will examine the function of α-tubulin deacetylating enzyme, HDAC6, and the α-tubulin acetylating enzyme, αTAT1, in SGNs. Using multiple innovative strategies, we will demonstrate that SGNs exhibit dynamic changes in post-translational modifications of tubulin. We will demonstrate unequivocally that the changes in acetylation of α-tubulin influence the outcome of SGN neurite outgrowth and innervation.
Specific Aim 1: Determine the extent to which increasing α-tubulin acetylation protects SGNs from excitotoxicity.
Specific Aim 2: Determine the extent to which α-tubulin acetylation increases axonal transport of mitochondria and mRNA.