Abstract
In 2012, our research group reported that HINT1 is associated with Charcot-Marie-Tooth neuropathy (CMT), the most common genetic disorder of the peripheral nerves. Mutations in HINT1 contribute significantly to the CMT morbidity, however, the mechanisms triggered by the loss of HINT1 function are unknown. The encoded protein is a ubiquitous purine phosphoramidase acting as a transcriptional regulator, but the physiological role of HINT1 in peripheral neurons and its connection to disease is unclear. In this project, I will take advantage of unique patient biomaterials and fly models to understand the tissue-specific nature of HINT1 neuropathy and translate this knowledge into therapeutic opportunities for CMT. I will perform an unbiased, spatially-defined differential profiling of the neuronal transcriptome at the site of CMT lesion and compare it to non-neuronal tissues from the same patients, and to controls. Endogenous HINT1 and related proteins will also be profiled in patients and controls. The bioinformatics integration of omics data will reveal components of neuronal pathways misregulated by the HINT1 deficiency and will guide selection of key molecules to be evaluated genetically and pharmacologically for their therapeutic potential in HINT1-KO fly model and patient-derived iPSC-motoneurons. Altogether, my findings will deliver mechanistic insights into the HINT1 function and related neurodegeneration, and will provide tangible opportunities for therapy development.
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