Immunoregulation in CNS remyelination

项目摘要 多发性硬化（MS）中髓鞘再生失败导致进行性轴突缺失 和累积残疾。我们以前已经发现白细胞介素-4诱导一种（IL 4 i1）， 一种巨噬细胞分泌的免疫调节酶，用于分解L-氨基酸， 调节炎症以促进小鼠中枢神经系统（CNS）中的髓鞘再生。 此外，我们发现IL 4 i1通过减少促炎性CD 4 + Th 1细胞来促进髓鞘再生， 和Th 17细胞活性。IL 4 i1如何对病变发挥作用 髓鞘再生过程中的微环境仍然未知。然而，IL 4 i1的需求在 髓鞘再生表明，一个以前未知的机制，涉及氨基酸代谢， 在中枢神经系统损伤中起作用，控制炎症并促进修复。在这里，我们假设， CNS损伤中氨基酸代谢的调节对于髓鞘再生的成功至关重要。到 为此，我们将分析在治疗过程中CNS病变中的氨基酸水平。 通过质谱分析髓鞘再生（目的1），确定氨基酸转运是否 需要调节炎症和髓鞘再生（目标2），并确定是否调节 氨基酸代谢影响髓鞘再生效率（目的3）。这项研究的结果，如果 成功，将阐明氨基酸代谢对中枢神经系统免疫细胞的作用 髓鞘再生，并导致氨基酸代谢调节剂作为潜在的未来研究 用于改善MS中髓鞘再生的治疗剂。

Project Summary Failure to regenerate myelin in multiple sclerosis (MS) contributes to progressive axonal loss and accumulated disability. We have previously found that interleukin-four induced one (IL4i1), a macrophage-secreted immunoregulatory enzyme that serves to breakdown L-amino acids, modulates inflammation to promote remyelination in the mouse central nervous system (CNS). Moreover, we found that IL4i1 promotes remyelination by reducing pro-inflammatory CD4+ Th1 and Th17 cell activity in CNS lesions. Exactly how IL4i1 exerts its effect on the lesion microenvironment during remyelination remains unknown. However, the requirement for IL4i1 in remyelination suggests that a previously unknown mechanism involving amino acid metabolism operates in CNS lesions to control inflammation and promote repair. Here, we hypothesize that the regulation of amino acid metabolism in CNS lesions is critical for remyelination success. To this end, we will profile the levels of amino acids in CNS lesions over the course of remyelination by mass spectrometry analysis (Aim 1), determine if amino acid transport is required to regulate inflammation and remyelination (Aim 2), and determine if modulators of amino acid metabolism affects remyelination efficiency (Aim 3). The results of this study, if successful, will elucidate the role of amino acid metabolism on immune cells in CNS remyelination, and lead to future studies on modulators of amino acid metabolism as potential therapeutics for improving remyelination in MS.