Novel strategies to promote nerve regeneration in diabetes

周围神经病变主要影响感觉和自主神经系统，是糖尿病常见的并发症，具有重要的临床意义。它经常导致感觉丧失、感觉异常和慢性疼痛。此外，糖尿病严重损害了周围神经再生受损轴突的能力，从而对神经系统造成了“双重打击”。特别是，神经损伤后的自发性恢复通常发生在非糖尿病人身上，糖尿病严重损害了这种恢复。这种再生失败的分子机制尚不清楚，目前还没有有效的治疗方法来改善功能恢复。GSK3抑制CRMP2磷酸化是中枢神经系统轴突再生失败的内在因素。虽然这种抑制性磷酸化通常不会发生在周围神经的轴突中，但我们发现它在糖尿病小鼠中被诱导，这表明这种磷酸化参与了损害糖尿病轴突再生的过程。本资助申请旨在通过细胞培养和不同的体内模型来深入研究这一新的假设，并探索潜在的分子机制。基于这些发现，本研究的目标是开发和测试新的治疗方法，以提高周围神经的再生能力，克服再生失败，特别是在糖尿病中。

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.