Immunoregulation in CNS remyelination

中枢神经系统髓鞘再生中的免疫调节

• 批准号: 9926930
• 负责人: Jeffrey K Huang
• 金额: $ 34.02万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9926930
• 关键词: Address; Adult; Affect; Amino Acid Transporter; Amino Acids; Ammonia; Astrocytes; Axon; Biochemical; CD4 Positive T Lymphocytes; Cell Differentiation process; Cell Lineage; Cell Proliferation; Cell physiology; Cells; Chronic; Cytomegalovirus; Data; Demyelinating Diseases; Demyelinations; Dissection; Dyes; Electron Microscopy; Enzyme-Linked Immunosorbent Assay; Enzymes; FRAP1 gene; Failure; Fibroblasts; Flow Cytometry; Future; Human; Hydrogen Peroxide; Immune; Immunology procedure; Inflammation; Inflammatory; Injections; Interferon Type II; Interleukin-17; Interleukins; Keto Acids; Knowledge; Label; Lead; Lesion; Lymphocyte; Lymphocyte Function; Lymphocyte Subset; Lysophosphatidylcholines; Mass Spectrum Analysis; Mediating; Methods; Multiple Sclerosis; Mus; Myelin; Natural regeneration; Neuraxis; Neutral Amino Acid Transport Systems; Neutral Amino Acids; Nude Mice; Oligodendroglia; Oxidases; Patients; Peripheral Blood Mononuclear Cell; Pharmacology; Phenylalanine; Population; Proliferating; Proteins; Proteomics; Quantitative Reverse Transcriptase PCR; Recombinants; Regulation; Resolution; Role; Signal Transduction; Spinal Cord; T-Lymphocyte; Tamoxifen; Testing; Therapeutic; Tissues; Transcript; Transplantation; Wild Type Mouse; amino acid metabolism; disability; immunoregulation; improved; in vivo; loss of function; macrophage; metabolomics; multiple sclerosis patient; novel; oligodendrocyte lineage; progressive neurodegeneration; remyelination; repaired; research and development; success; transcriptomics

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.

项目摘要 多发性硬化症(MS)髓鞘再生失败导致进行性轴突丢失 和累积的残疾。我们先前已经发现，白介素4诱导了一种(IL4I1)， 一种巨噬细胞分泌的免疫调节酶，用于分解L的氨基酸， 调节炎症以促进小鼠中枢神经系统(CNS)的重新髓鞘形成。 此外，我们还发现，IL4i1通过减少促炎的CD4+Th1来促进髓鞘再生 中枢神经系统病变的Th17细胞活性。IL4i1究竟是如何在病变中发挥作用的 髓鞘再分化过程中的微环境尚不清楚。但是，中对IL4i1的要求 重新髓鞘形成表明了一种以前未知的涉及氨基酸代谢的机制 在中枢神经系统损伤中发挥作用，控制炎症，促进修复。在这里，我们假设 中枢神经系统损伤中氨基酸代谢的调节是髓鞘再生成功的关键。至 为此，我们将分析中枢神经系统损伤过程中的氨基酸水平。 通过质谱分析重新髓鞘形成(目标1)，确定氨基酸转运是否 调节炎症和重新髓鞘形成所需的(目标2)，并确定 氨基酸代谢影响再髓鞘形成效率(目标3)。这项研究的结果，如果 成功，将阐明氨基酸代谢在中枢神经系统免疫细胞中的作用 重新髓鞘形成，并导致未来对氨基酸代谢调节剂的潜在研究 改善多发性硬化髓鞘再生的治疗方法