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Role of GPNMB signaling in remyelination by oligodendrocyte progenitor cells

GPNMB 信号在少突胶质祖细胞髓鞘再生中的作用

基本信息

批准号：
10431034
负责人：
Jayshree Samanta
金额：
$ 7.78万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
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：
2022-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10431034
关键词：
Ablation Adult Affect Astrocytes Autocrine Communication Bioinformatics Brain CD44 gene CSPG4 gene Cell Count Cell Maturation Cell Nucleus Cells Chronic Clinical Corpus Callosum Cuprizone Data Demyelinating Diseases Demyelinations Diet Disease Glycoproteins Harvest Human Immune In Vitro Integral Membrane Protein Knock-in Mouse Knock-out Knockout Mice LacZ Genes Lead Lesion Longevity LoxP-flanked allele Mediating Mediator of activation protein Microglia Modeling Molecular Multiple Sclerosis Mus Neonatal Nerve Degeneration Nonmetastatic Oligodendroglia Outcome Paracrine Communication Pathway interactions Peptide Hydrolases Recombinants Regulation Role Signal Transduction Source Testing aging brain axonal degeneration cell type chronic demyelination dosage glycoprotein NMB human disease in vivo insight nerve stem cell novel oligodendrocyte progenitor overexpression peripheral blood prevent receptor remyelination response stem cells subventricular zone therapeutic target transcriptome sequencing transcriptomics

项目摘要

ABSTRACT Loss of oligodendrocytes gives rise to demyelination, ultimately resulting in axonal degeneration and debilitating clinical outcomes in diseases like Multiple Sclerosis. While remyelination can prevent neurodegeneration, there are currently no approved therapies for promoting remyelination. Thus, there is an urgent need to identify factors that control remyelination. Oligodendrocyte progenitor cells (OPCs) in the adult brain are one of the key sources of remyelinating oligodendrocytes. However in chronic demyelination, they are inefficient for remyelination due to depletion and/or a block in their maturation. Using a combination of bioinformatic analysis and remyelination studies in mice, we discovered a novel mediator of the 7*)? pathway, Gpnmb which is highly expressed along with its receptor CD44 in response to demyelination. Gpnmb is a transmembrane protein that is cleaved by proteases into an intracellular domain (Gpnmb-ICD) and an ectodomain (Gpnmb-ECD). While Gpnmb-ICD can signal intrinsically by translocating to the nucleus, the released Gpnmb-ECD functions as an autocrine or paracrine signal by interacting with CD44 receptor in the same cell or a neighboring cell respectively. In the first aim, we will define the cell-autonomous function of Gpnmb in oligodendrocyte progenitor cells and in the second aim, we will determine the combined effect of intrinsic and extrinsic Gpnmb signaling on OPCs following cuprizone induced demyelination. Together, these studies will not only help elucidate the molecular mechanisms involved in maturation of adult OPCs but may also identify therapeutic targets for promoting remyelination.

摘要