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Novel Modulators of TGFß1 signaling in regulation of remyelination by neural stem cells

TGFα1 信号传导在神经干细胞髓鞘再生调节中的新型调节剂

基本信息

批准号：
10544041
负责人：
Jayshree Samanta
金额：
$ 38.21万
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：
2022-01-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10544041
关键词：
Ablation Adult Binding Sites Bioinformatics Brain CD44 gene Cell Culture Techniques Cells Choline Chronic Clinical Corpus Callosum Cuprizone Data Demyelinating Diseases Demyelinations Diet Disease Exhibits Gene Expression Genes Glycoproteins Human In Vitro Injections Knock-out Knockout Mice Lesion Ligands LoxP-flanked allele Mediating Mediator Modeling Molecular Multiple Sclerosis Mus Nerve Degeneration Nonmetastatic Oligodendroglia Outcome Pathway interactions Population Heterogeneity Promoter Regions Recovery of Function Regulation Reporting Role Signal Pathway Signal Transduction Source Testing Toxin Transforming Growth Factor beta Work axonal degeneration cell type differential expression dosage extracellular glycoprotein NMB human disease in vivo insight melanoma multiple sclerosis patient nerve stem cell novel overexpression paracrine peripheral blood prevent receptor receptor binding recruit remyelination repaired response subventricular zone therapeutic target transcription factor 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. Neural stem cells in the adult subventricular zone are one of the sources of remyelinating oligodendrocytes. These cells are a heterogeneous population that show diverse responses to signaling pathways in the healthy vs demyelinated brain. We have studied one such pool marked by Gli1, which generates remyelinating oligodendrocytes only in response to demyelination. Our previous work showed that the recruitment and differentiation into oligodendrocytes leading to functional recovery is increased substantially by loss of Gli1 in this pool of neural stem cells; however the molecular mechanisms involved in this repair is not known. Through a transcriptomic analysis comparing gene expression in neural stem cells with and without Gli1 expression, we identified the TGFβ1 pathway as a major regulator of remyelination mediated by neural stem cells. However, the effects of TGFβ1 signaling are context dependent and differ with the cell-type, timing and dosage suggesting the presence of specific modulators of the pathway in different cells. Using a combination of bioinformatic analysis and remyelination studies in mice, we discovered a novel mediator of the TGFβ1 pathway, Gpnmb which is highly expressed along with its receptor CD44 in neural stem cells in response to demyelination. In the first aim, we will define the cell-autonomous function of Gpnmb in neural stem cells and its role in remyelination by neural stem cells. In the second aim, we will determine the impact of paracrine Gpnmb signaling through CD44 receptor on remyelination mediated by neural stem cells. In the third aim, we will elucidate the mechanisms of regulation of Gpnmb by TGFβ1 ligand and reciprocal modulation of the TGFβ1 pathway by Gpnmb. For the remyelination studies, we will use the toxin induced models of demyelination. To define the molecular mechanisms of the TGFβ1-Gpnmb signaling pathway, we will utilize in vitro neural stem cell cultures from adult mouse brain. Together, these studies will help identify therapeutic targets for promoting remyelination.

抽象的少突胶质细胞的丧失会导致脱髓鞘，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。虽然髓鞘再生可以预防神经退行性变，但目前尚无批准的促进髓鞘再生的疗法。因此，迫切需要找出影响因素控制髓鞘再生。成人脑室下区的神经干细胞是神经干细胞的来源之一。髓鞘再生少突胶质细胞。这些细胞是异质群体，对不同的反应表现出不同的反应健康大脑与脱髓鞘大脑中的信号通路。我们研究了这样一个由 Gli1 标记的池，它仅在脱髓鞘反应中产生髓鞘再生少突胶质细胞。我们之前的工作表明少突胶质细胞的募集和分化导致功能恢复显着增加该神经干细胞库中 Gli1 缺失；然而，参与这种修复的分子机制并不已知。通过转录组分析比较有和没有 Gli1 的神经干细胞中的基因表达表达，我们确定 TGFβ1 途径是神经干介导的髓鞘再生的主要调节因子细胞。然而，TGFβ1 信号传导的影响取决于环境，并且因细胞类型、时间和作用而异。剂量表明不同细胞中存在该途径的特定调节剂。使用组合通过对小鼠的生物信息分析和髓鞘再生研究，我们发现了一种新型的 TGFβ1 通路介质， Gpnmb 与其受体 CD44 一起在神经干细胞中高度表达，以响应脱髓鞘作用。第一个目标是定义 Gpnmb 在神经干细胞中的细胞自主功能及其在神经干细胞中的作用。神经干细胞的髓鞘再生。在第二个目标中，我们将确定旁分泌 Gpnmb 信号传导的影响通过CD44受体介导神经干细胞的髓鞘再生。在第三个目标中，我们将阐明 TGFβ1配体调节Gpnmb的机制以及TGFβ1途径的相互调节 GPnmb。对于髓鞘再生研究，我们将使用毒素诱导的脱髓鞘模型。定义 TGFβ1-Gpnmb 信号通路的分子机制，我们将利用体外神经干细胞培养物来自成年小鼠的大脑。总之，这些研究将有助于确定促进髓鞘再生的治疗靶点。