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，这会阻碍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和巨噬细胞中细胞内Ca2+的增加有关在脊髓根部积聚。施用Ca2+螯合剂可抑制图4 - / - 小鼠中的脱髓鞘。因此，该小鼠成为研究基础事件的出色模型脱髓鞘。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，导致节段脱髓鞘。我们提出了三个具体目标：（1）缺乏的雪旺细胞对在CA2+挑战时脱髓鞘；（2）缺陷巨噬细胞释放触发的细胞因子IL12b 无缺陷的雪旺细胞中细胞内Ca2+的进一步增加，导致脱髓鞘。（3）个人 PAS复合物中的蛋白质在髓磷脂和轴突的发育和维持中具有不同的作用。这些研究将有可能发现脱髓鞘的新分子机制周围神经病并确定治疗性发育的靶标。