Novel strategies to promote nerve regeneration in diabetes

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Peripheral neuropathy mainly affects the sensory and autonomic nervous system and is a common complication of diabetes mellitus with significant clinical magnitude. It often leads to sensory loss, paresthesia and chronic pain. In addition, diabetes substantially compromises the ability of peripheral nerves to re-generate injured axons thereby imposing a ‘double hit’ on the nervous system. In particular, the sponta-neous recovery after nerve injuries that can typically occur in non-diabetic humans is severely impaired by diabetes. The molecular mechanisms underlying this regenerative failure is still unclear and effective treatments to improve functional recovery are not currently available. Inhibitory phosphorylation of CRMP2 by GSK3 is an intrinsic contributor to the regenerative failure of axons of the central nervous system. While this inhibitory phosphorylation does not normally occur in axons of peripheral nerves, we found that it is induced in diabetic mice, suggesting that this phosphorylation is involved in compromising axon regeneration in diabetes. This grant application aims to thoroughly investigate this novel hypothesis and to explore the underlying molecular mechanisms using cell culture and in different vivo models. Based on these findings, the goal of this study is the development and testing of novel treatments to improve the regenerative capacity of peripheral nerves and overcome regenerative failure, particularly in diabetes.