Regulation of Schwann cell enshealthment and myelination by type III Neuregulin 1

III 型神经调节蛋白 1 对雪旺细胞健康和髓鞘形成的调节

基本信息

批准号：
8675621
负责人：
JAMES SALZER
金额：
$ 35.65万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-11 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8675621
关键词：
1-Phosphatidylinositol 3-Kinase Address Axon Back Binding Cell Culture Techniques Cell Lineage Cell Survival Cellular biology Cleaved cell Coculture Techniques Complex Cytoplasmic Tail Disease Event Fiber Genetic Genetic Transcription Goals Growth Factor Knock-out Lead MAP Kinase Signaling Pathways Maintenance Membrane MicroRNAs Modeling Mus Myelin Myelin Proteins Myelin Sheath Nerve Nerve Fibers Neuregulin 1 Neurons Neuropathy Pathogenesis Pathway interactions Phenotype Protein Isoforms Proteins Raptors Regulation Research Role Schwann Cells Signal Pathway Signal Transduction Sirolimus Testing Transgenes Transgenic Mice Transgenic Organisms Translations human FRAP1 protein in vivo insight mouse model myelination neuronal growth neuronal survival novel therapeutics programs protein expression receptor remyelination repaired segregation transcription factor

项目摘要

The long term goal of this research program is to elucidate how axons drive Schwann cell ensheathment and myelination. We are investigating the role of neuregulin-1 (NRG1), a neuronal growth factor which regulates the entire Schwann cell lineage, including the binary choice between ensheathment and myelination in the PNS. The mechanisms by which type III NRG1 drives Schwann cell ensheathment and myelination remain poorly understood. NRG1 binds to erbB receptors on Schwann cells, activating the PI 3-kinase, PLC-3, and MAP kinase signaling pathways. Our general model is that Schwann cell survival, ensheathment and myelin wrapping all require NRG1-dependent activation of PI 3-kinase whereas other signaling pathways may drive the sequential expression of myelin-specific transcription factors (TFs). Using a recently generated transgenic mouse that expresses an activated, membrane targeted form of Akt1, we will investigate further how NRG1 drives axon ensheathment, myelination, and survival. Specifically, we will: i) investigate whether Akt is a primary effector of PI 3-kinase- dependent survival and ensheathment by analyzing mice deficient in Akt isoforms and by expressing activated Akt in Schwann cells interacting with NRG1 deficient neurons, ii) characterize the role(s) of the TORC1 and TORC2 pathways in ensheathment and myelination, and iii) analyze whether Akt cooperates with other signals, including NFAT, during myelination, by crossing transgenic mice expressing activated Akt and NFAT transgenes and examine potential cooperative effects on myelination. These studies should provide important insights into how type III NRG1 on the axon drives survival, ensheathment and myelination by Schwann cells. Relevance: These studies seek to identify signals that promote myelin sheath formation, the cellular insulation that surrounds nerve fibers and is critical for their proper function and long term integrity. Findings in this study may therefore have important implications for the pathogenesis of disorders of myelinated fibers, including neuropathies, and lead to new therapeutic strategies to promote their repair.

该研究计划的长期目标是阐明轴突如何驱动Schwann细胞的启动和髓鞘化。我们正在研究Neuregulin-1（NRG1）的作用，该神经元生长因子调节了整个Schwann细胞谱系，包括PNS中的套装和髓鞘化之间的二元选择。 III型NRG1驱动Schwann细胞宿内和髓鞘形成的机制仍然很少了解。 NRG1与Schwann细胞上的ERBB受体结合，激活PI 3-激酶，PLC-3和MAP激酶信号通路。我们的一般模型是，Schwann细胞的存活，套装和髓磷脂包裹都需要NRG1依赖性PI 3-激酶的激活，而其他信号通路可能会驱动髓磷脂特异性转录因子（TFS）的顺序表达。使用最近生成的转基因小鼠，该小鼠表达Akt1的激活的膜靶向形式，我们将进一步研究NRG1如何驱动轴突的套筒，髓鞘形成和存活。具体而言，我们将：i）调查AKT是否是PI 3-激酶依赖生存和启动的主要效应因子，通过分析小鼠在Akt同工型中缺乏小鼠，并通过表达与NRG1缺陷神经元相互作用的Schwann细胞中激活的AKT，与NRG1缺陷的神经元相互作用。通过跨越表达活化的Akt和NFAT转基因的转基因小鼠，与其他信号（包括NFAT）合作，并检查对髓鞘化的潜在合作作用。这些研究应提供有关轴突上III型NRG1如何驱动Schwann细胞生存，包裹和髓鞘形成的重要见解。相关性：这些研究旨在识别促进髓鞘形成的信号，这是围绕神经纤维的细胞绝缘材料，对于它们的正常功能和长期完整性至关重要。因此，这项研究的发现可能对包括神经病在内的髓纤维疾病的发病机理具有重要意义，并导致新的治疗策略来促进其修复。