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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.

摘要少突胶质细胞的损失引起脱髓鞘，最终导致轴突变性和衰弱。多发性硬化症等疾病的临床结果。虽然髓鞘再生可以防止神经变性，目前还没有批准的促进髓鞘再生的疗法。因此，迫切需要查明各种因素，控制髓鞘再生成人大脑中的少突胶质祖细胞（OPCs）是关键来源之一髓鞘再生少突胶质细胞然而，在慢性脱髓鞘中，它们对髓鞘再生无效，耗尽和/或阻断其成熟。结合生物信息学分析和髓鞘再生在小鼠的研究中，我们发现了一种新的介体7*）？途径，Gpnmb，它是高表达的沿着其受体CD 44对脱髓鞘的反应。GPNMB是一种跨膜蛋白，在一个实施方案中，所述蛋白酶被编码为胞内结构域（Gpnmb-ICD）和胞外域（Gpnmb-ECD）。虽然Gpnmb-ICD可以通过易位到细胞核内在地发出信号，释放的Gpnmb-ECD作为自分泌或通过分别与同一细胞或相邻细胞中的CD 44受体相互作用来产生旁分泌信号。上目的是，我们将确定Gpnmb在少突胶质细胞祖细胞中的细胞自主功能，我们的目的是确定内源性和外源性Gpnmb信号转导对OPCs的联合作用，铜腙诱导的脱髓鞘。总之，这些研究不仅有助于阐明参与成年OPCs的成熟，但也可能确定促进髓鞘再生的治疗靶点。