Pathogenesis in Segmental Demyelination

节段性脱髓鞘的发病机制

• 批准号: 10739061
• 负责人: Bo Hu
• 金额: $ 40.38万
• 依托单位: METHODIST HOSPITAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10739061
• 关键词: Action Potentials; Axon; Cells; Charcot-Marie-Tooth Disease; Chelating Agents; Complex; Cytoplasm; Demyelinating Polyneuropathy; Demyelinations; Development; Diphosphates; Disease; Endosomes; Event; Failure; Functional disorder; Genes; Human; IL12B gene; Impairment; In Vitro; Individual; Inflammatory; Interleukin-1; Interleukin-12; Knock-out; Macrophage; Maintenance; Membrane; Modeling; Molecular; Molecular Target; Mus; Mutation; Myelin; Myelin Sheath; Neurons; Neuropathy; Pathogenesis; Pathologic; Pathologic Processes; Pathology; Pathway interactions; Patients; Peripheral Nerve Sheath; Peripheral Nervous System Diseases; Phosphatidylinositols; Phosphoric Monoester Hydrolases; Phosphotransferases; Play; Principal Investigator; Process; Proteins; Publications; Recombinants; Role; Scaffolding Protein; Schwann Cells; Shunt Device; Signal Transduction; Spinal nerve root structure; Stem Cell Factor; Testing; Text; autosome; axonal degeneration; cell type; cytokine; in vivo; inorganic phosphate; loss of function; lysosome membrane; mouse model; myelination; neurotransmission; novel; programs; targeted treatment; therapeutic development; therapy development; trafficking; transcriptome sequencing

Project Summary Abstract: Segmental demyelination is a pathologic process of stripping off the myelin sheath, which shunts current out of axons and results in the failure of action potential propagation in a variety of peripheral nerve diseases. However, the molecular program that leads to the demyelination remains unclear, which hampers the therapeutic development for demyelinating neuropathies. Humans with autosomal recessive mutations in FIG4 gene develop Charcot-Marie-Tooth disease type-4J (CMT4J), a disease characterized by segmental demyelination. Our preliminary studies in a CMT4J mouse model (Fig4−/−) have demonstrated that segmental demyelination is associated with increased intracellular Ca2+ in myelinating Schwann cells and macrophages accumulation in the spinal roots. Administering a Ca2+ chelator suppresses the demyelination in Fig4−/− mice. Therefore, this mouse becomes an excellent model to investigate the molecular events underlying demyelination. Toward this end, we will test our central hypothesis that signals from FIG4-deficient axons and/or macrophages exacerbate the overload of intracellular Ca2+ in FIG4-deficient Schwann cells, leading to segmental demyelination. We propose three Specific Aims: (1) FIG4-deficient Schwann cells are sensitized to demyelinate upon challenge with Ca2+; (2) FIG4-deficient macrophages release cytokine IL12B that triggers further increases in intracellular Ca2+ in FIG4-deficient Schwann cells, leading to demyelination; (3) Individual proteins in the PAS complex have different roles in the development and maintenance of myelin and axons. These studies will have the potential to uncover novel molecular mechanisms underlying demyelinating peripheral neuropathies and identify targets for therapeutic development.

项目概要 摘要：节段性脱髓鞘是髓鞘剥离、分流的病理过程。 电流流出轴突，导致多种周围神经动作电位传播失败 疾病。然而，导致脱髓鞘的分子程序仍不清楚，这阻碍了 脱髓鞘性神经病的治疗进展。患有常染色体隐性突变的人类 Fig4 基因发展为 4J 型腓骨肌萎缩症 (CMT4J)，一种以节段性为特征的疾病 脱髓鞘。我们对 CMT4J 小鼠模型（图 4−/−）的初步研究表明，节段性 脱髓鞘与有髓鞘雪旺细胞和巨噬细胞中细胞内 Ca2+ 增加有关 积聚于脊根。施用 Ca2+ 螯合剂可抑制 Fig4−/− 小鼠的脱髓鞘。 因此，这只小鼠成为研究潜在分子事件的优秀模型 脱髓鞘。为此，我们将测试我们的中心假设，即来自Fig4缺陷轴突的信号 和/或巨噬细胞加剧了Fig4缺陷雪旺细胞中细胞内Ca2+的超载，导致 节段性脱髓鞘。我们提出了三个具体目标：（1）FIG4 缺陷的雪旺细胞对 Ca2+ 激发后脱髓鞘； (2)Fig4缺陷型巨噬细胞释放细胞因子IL12B，触发 Fig4缺陷雪旺细胞中胞内Ca2+进一步增加，导致脱髓鞘； (3) 个人 PAS 复合体中的蛋白质在髓磷脂和轴突的发育和维持中发挥不同的作用。 这些研究将有可能揭示脱髓鞘的新分子机制 周围神经病变并确定治疗开发的目标。