Pathogenesis in Segmental Demyelination

节段性脱髓鞘的发病机制

基本信息

批准号：
10518833
负责人：
Bo Hu
金额：
$ 38.5万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-15 至 2022-07-17
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10518833
关键词：
Action Potentials Axon Calcium Charcot-Marie-Tooth Disease Chelating Agents Complex Demyelinating Diseases Demyelinating Polyneuropathy Demyelinations Development Diphosphates Disease Endosomes Event Failure Functional disorder Genes Human IL12B gene Impairment In Vitro Individual Inflammatory Knock-out Lysosomes 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 Recombinants Role Scaffolding Protein Schwann Cells Shunt Device Signal Transduction Spinal nerve root structure Testing axonal degeneration cell type cytokine in vivo inorganic phosphate loss of function lysosome membrane macrophage mouse model myelination neurotransmission novel novel therapeutics prevent programs targeted treatment therapeutic development therapy development trafficking transcriptome sequencing

项目摘要

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 demyelination remains unclear, which hampers the therapeutic development for demyelinating neuropathies. Humans with autosomal recessive mutations in the 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 accumulation of macrophages in the spinal roots. Administration of a Ca2+ chelator suppresses the demyelination in Fig4−/− mice. Therefore, this mouse is an appropriate 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 which, in turn, leads to segmental demyelination. We propose three Specific Aims to test our hypothesis by determining if: (1) FIG4-deficient Schwann cells are sensitized to demyelinate upon challenge with Ca2+; (2) FIG4-deficient macrophages release cytokine IL12B that triggers a further increase in intracellular Ca2+ in FIG4-deficient Schwann cells, leading to demyelination; and (3) individual proteins in the PAS complex play distinct roles in the development and maintenance of myelin and axons. These studies 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然而，导致脱髓鞘的分子程序仍不清楚，这阻碍了脱髓鞘的发展。患有常染色体隐性突变的人类脱髓鞘性神经病的治疗开发。 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我们在 CMT4J 小鼠模型中的初步研究（图 4−/−）已经证明节段性脱髓鞘作用。脱髓鞘与有髓鞘雪旺细胞中细胞内 Ca2+ 的增加和积累有关脊髓根部巨噬细胞的施用 Ca2+ 螯合剂抑制图 4−/− 中的脱髓鞘。因此，该小鼠是研究分子基础事件的合适模型。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，我们提出了三个具体目标来通过确定来检验我们的假设。如果： (1) Fig4 缺陷型雪旺细胞在 Ca2+ 攻击后变得敏感脱髓鞘 (2) Fig4 缺陷型；巨噬细胞释放细胞因子 IL12B，引发 Fig4 缺陷型细胞内 Ca2+ 进一步增加雪旺细胞，导致脱髓鞘；(3) PAS 复合物中的各个蛋白质在这些研究有可能发现新的髓磷脂和轴突的发育和维持。脱髓鞘性周围神经病的分子机制并确定治疗靶点发展。