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Project

HINT1 neuropathies - identification of disease pathways and therapeutic targets.

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 purine phosphoramidase, but the physiological role of HINT1 in neurons and its connection to disease is unclear. In this project, we will take advantage of the evolutionary conservation of HINT1 function and will integrate studies in yeast and human cells to understand how mutations in HINT1 lead to CMT. In a genetic complementation screen we will search for neuronally-expressed human genes rescuing Hnt1 deficiency in yeast. Also, we will create and characterize patient-derived motor neurons and will perform transcriptomics on them to identify disease-specific mis-regulated transcripts. The results obtained with these complementary approaches will allow us to build the HINT1 regulatory network in neuronal cells. Finally, we will pharmacologically target druggable components of the HINT1 network to provide a proof of concept. Altogether, this study will decipher the fundamental role of HINT1 in neuronal homeostasis, will provide mechanistic insights on HINT1-related CMT, and will give tangible clues for designing therapeutic strategies.
Date:1 Jan 2017 →  31 Dec 2020
Keywords:GENETICS
Disciplines:Genetics, Systems biology, Molecular and cell biology