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.

项目摘要摘要：分段脱髓鞘是脱落髓鞘的病理学过程，该过程可分流电流从轴突出发，导致各种周围神经的动作电位传播失败疾病。但是，导致脱髓鞘的分子程序尚不清楚，这阻碍了脱髓鞘神经病的治疗发展。患有常染色体隐性突变的人 FIG4基因发育Charcot-Marie-Tooth疾病型4J（CMT4J），一种以节段为特征的疾病脱髓鞘。我们在CMT4J小鼠模型中的初步研究（图4 - / - ）证明了节段脱髓鞘与髓鞘的雪旺细胞中细胞内Ca2+的增加有关，并积累脊髓根中的巨噬细胞。施用Ca2+螯合剂可抑制图4 - / - 中的脱髓鞘老鼠。因此，该小鼠是研究基础事件的合适模型脱髓鞘。为此，我们将测试中心假设，即来自FIG4缺陷轴突的信号和/或巨噬细胞加剧细胞内Ca2+在无缺的雪旺细胞中的过载转弯，导致分段脱髓鞘。我们提出了三个特定的目的，以通过确定来检验我们的假设 if：（1）缺乏Fig4的雪旺细胞对Ca2+挑战时对脱髓鞘的敏感；（2）无缺陷巨噬细胞释放细胞因子IL12B，该IL12B触发了无缺陷型细胞内Ca2+的进一步增加 Schwann细胞，导致脱髓鞘；（3）PAS复合物中的单个蛋白质在髓磷脂和轴突的发育和维护。这些研究有可能发现新颖分子机制是脱髓鞘周围神经病的基础，并识别治疗靶标发展。