免疫相关GTP酶家族成员IRGM介导的神经元自噬在急性中枢神经系统损伤和修复中的作用研究

Autophagy can regulate cell homeostasis through degradation of unnecessary cellular component, which is an important compensatory mechanism. Recently, a series studies from our lab and other groups have shown that autophagy is also crucial for the neuron. Using various animal model of ischemia, we found that ischemia can induce massive neuronal autophagy, which is vital for neuron survival. Furthermore, our study has identified a novel molecule called IRGM1, a member of small GTPase family, can regulate neuronal autophagy during ischemia. However, the relationship between neuronal autophagy and other reasons induced neuron injury such as trauma, and how it can impact neural regeneration after injury are still not clear. Furthermore, the molecular mechanisms underlying neuronal autophagy is still not fully understood. So in this project, we aim to investigate the role of neuronal autophagy in different stage of neural injury and regeneration. With focus on IRGM1, we also want to identify the molecular mechanism that regulates neuronal autophagy. To answer these questions properly is not only important for better understanding the mechanism of neural injury and regeneration, but may also provide new direction for developing therapy.

细胞自噬通过消化细胞内固有成分以维持细胞稳态，是细胞重要的代偿机制。近几年来，我们和其他实验室的系列研究发现这一机制对于'脆弱'的神经细胞来说尤为重要。应用不同缺血性脑损伤实验模型先后证实：缺血损伤能够诱发神经细胞发生大量自噬，并能有效调节损伤神经元生存和死亡方式。我们在前期研究中发现免疫相关性GTP酶家族成员IRGM1可促进缺血引起的神经细胞自噬反应，从而减少缺血性神经元死亡，减少缺血性脑卒中的梗死面积。然而，IRGM1介导神经元自噬调节的具体分子机制未能阐明，其是否与其他原因（如外伤）引起的急性神经细胞损伤及损伤后修复也相关亦未见报道。本项目将在前期研究工作基础上，比较在不同原因引起的急性神经损伤中，神经元自噬对于神经损伤和修复的影响，以及IRGM1在其中的关键性调节作用及其分子通路。研究结果将从全新的角度阐明急性神经元损伤及修复机制，并可能为急性神经损伤的诊断治疗提供新的思路。

IRGM/Irgm1是免疫相关GTP酶家族的重要成员。我们的前期工作提示IRGM/Irgm1作为细胞自噬的重要调节因子在损伤的神经元表达升高。本项目以此为起点，对IRGM/Irgm1及其介导的神经元自噬在机械性和缺血性神经损伤中的作用进行深入研究。我们发现机械性和缺血性神经损伤都可以引起神经元自噬的发生。Irgm1基因缺陷小鼠的自噬水平却明显低于野生型小鼠，这提示IRGM/Irgm1对于这两类刺激神经元自噬至关重要。不仅如此，我们还发现缺少了IRGM/Irgm1介导的神经元自噬明显降低了神经元对抗应激环境的能力，继而进一步增加了神经元的损伤。此外，我们还首次发现了IRGM在人闭合性脑损伤以及缺血性脑卒中发生时，高表达于损伤的神经元。对于人类神经元的体外研究提示人IRGM同样对于神经元线粒体自噬起到至关重要的作用，而这种作用主要通过mitofilin-PINK1信号通路。这项研究的顺利完成不仅拓展了人们对于IRGM/Irgm1在神经损伤中的作用，明确了IRGM/Irgm1调控神经元自噬的分子机制，更为针对IRGM/Irgm1的临床应用提供了详实的实验基础。