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

• 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
• 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

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.

这项研究计划的长期目标是阐明轴突如何驱动雪旺细胞的包膜和髓鞘形成。我们正在研究神经调节蛋白-1(NRG1)的作用，NRG1是一种神经生长因子，调节整个雪旺细胞谱系，包括在PNS中在包膜和髓鞘形成之间的二元选择。III型NRG1驱动雪旺细胞包膜和髓鞘形成的机制仍然知之甚少。NRG1与雪旺细胞上的erbB受体结合，激活PI-3-K、PLC-3和MAP-K信号通路。我们的一般模型是，雪旺细胞的存活、包膜和髓鞘包裹都需要依赖于NRG1的PI 3-激酶的激活，而其他信号通路可能驱动髓鞘特异的转录因子(TF)的顺序表达。使用最近产生的表达激活的、膜靶向形式的Akt1的转基因小鼠，我们将进一步研究NRG1如何驱动轴突包膜、髓鞘形成和存活。具体地说，我们将：i)通过分析Akt亚型缺失的小鼠以及在与NRG1缺失的神经元相互作用的雪旺细胞中表达激活的Akt，探讨Akt是否是PI 3-K依赖的生存和包膜的主要效应因子；ii)研究TORC1和TORC2通路在髓鞘和髓鞘形成中的作用(S)；以及iii)通过杂交表达激活的Akt和NFAT转基因基因的转基因小鼠，分析Akt在髓鞘形成过程中是否与包括NFAT在内的其他信号进行合作，并研究在髓鞘形成方面可能的协同作用。这些研究应该为轴突上的III型NRG1如何驱动雪旺细胞的存活、包膜和髓鞘形成提供重要的见解。相关性：这些研究试图确定促进髓鞘形成的信号，髓鞘是围绕神经纤维的细胞绝缘，对其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有髓纤维疾病的发病机制具有重要意义，并导致促进其修复的新的治疗策略。