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Pathogenesis in Segmental Demyelination

节段性脱髓鞘的发病机制

基本信息

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
项目类别：
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

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 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.

项目总结