ELUCIDATING THE ROLE OF NEURONAL MTOR SIGNALING IN SCHWANN CELL DEVELOPMENT

阐明神经元 MTOR 信号转导在施万细胞发育中的作用

• 批准号: 9387143
• 负责人: Valeria Cavalli
• 金额: $ 19.06万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-15 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9387143
• 关键词: Address; Adult; Affect; Afferent Neurons; Affinity Chromatography; Agreement; Animal Behavior; Animal Testing; Astrocytes; Axon; Behavior; Biogenesis; Caliber; Cell physiology; Cellular biology; Charcot-Marie-Tooth Disease; Coupled; Defect; Development; Employee Strikes; Ensure; FRAP1 gene; Genetic; Genetic Transcription; Goals; Immunofluorescence Immunologic; Maintenance; Mediating; Messenger RNA; MicroRNAs; Molecular; Motor; Mus; Myelin; Myelin Sheath; Nerve; Neuroglia; Neurons; Nociception; Oligodendroglia; Pain; Perception; Peripheral Nerves; Peripheral Nervous System; Peripheral Nervous System Diseases; Protein Biosynthesis; Protein Kinase; Ribosomal Proteins; Ribosomes; Role; Schwann Cells; Sensory; Signal Transduction; Sorting - Cell Movement; Specificity; Structural defect; Supporting Cell; Systems Development; Thick; Time; Transgenic Organisms; Translating; Transmission Electron Microscopy; Tuberous Sclerosis; Unmyelinated Nerve Fibers; Validation; Viral; axonal degeneration; base; cell growth; cell type; chronic pain; excitatory neuron; experimental study; in vivo; insight; mouse model; mutant; myelination; nervous system disorder; neurotransmission; next generation sequencing; novel; novel therapeutics; painful neuropathy; sciatic nerve; sural nerve; transcriptome sequencing

Trophic support and myelination of axons by Schwann cells in the peripheral nervous system (PNS) are essential for normal nerve function. Disruptions to myelin result in many neurological diseases, including Charcot-Marie-Tooth disease and numerous other peripheral neuropathies. Aberrant Schwann cell physiology leads to axon degeneration, demonstrating that glial-derived signals are required for axonal integrity. Non- myelinating Schwann cells in peripheral nerves, known as Remak Schwann cells, surround and ensheath small diameter axons into “Remak bundles,” and structural defects in Remak bundles were shown to be associated with chronic pain. Schwann cell–axonal interactions are thus essential for proper nerve function, but the extent to which neurons contribute to Remak Schwann cell development is not well understood. In a mouse model of tuberous sclerosis, in which cortical neurons lack Tuberous sclerosis 1 (Tsc1), a negative regulator of the master regulator of protein synthesis, mTOR (mammalian Target Of Rapamycin), a striking delay in myelination was observed. Furthermore, loss of Tsc2, another negative regulator of mTOR, in excitatory neurons affects astrocyte development. These studies indicate that mTOR activation by neuronal deletion of Tsc1 or Tsc2 affects the development of glia, including oligodendrocytes and astrocytes. In agreement with these studies, our preliminary results in the peripheral nervous system indicate that in mice lacking Tsc2 in sensory neurons, Remak bundles are disorganized: the Remak bundles are oddly shaped and possess abnormally large diameter axons as well as fewer axons per bundle. We also noted thicker myelin around some axons and evidence of lost axon-Schwann cell contact. These results indicate that Tsc2 deletion and the resulting activation of mTOR in sensory neurons generates abnormal signals that disrupt Schwann cell development and/or maintenance, with a prominent effect on Remak bundles. Our goal is to understand the molecular mechanisms by which neuronal mTOR signaling impacts Schwann cells and Remak bundle organization. In Aim 1 we will expand and thoroughly define the consequence of Tsc2 deletion in sensory neurons on Schwann cell development and peripheral nerve function. In Aim 2, we will use genetic and next generation sequencing approaches to identify the molecular mechanisms underlying neuronally induced Schwann cell defects. These studies will help elucidate the role of axonally-derived signals in Remak Schwann cell development and may uncover new therapeutic avenues to treat peripheral neuropathy.

周围神经系统(PNS)中雪旺细胞对轴突的营养支持和髓鞘形成 对于正常的神经功能来说是必不可少的。髓鞘的破坏会导致许多神经系统疾病，包括 Charcot-Marie-Tooth病和许多其他周围神经病。异常雪旺细胞生理学 导致轴突退化，表明神经胶质信号是轴突完整所必需的。非- 周围神经中的髓鞘雪旺细胞，称为Remak雪旺细胞，环绕和包膜 小直径轴突形成“Remak束”，Remak束中的结构缺陷被证明是 与慢性疼痛有关。因此，雪旺细胞-轴突的相互作用对于正常的神经功能是必不可少的，但 神经元对Remak雪旺细胞发育的贡献程度尚不清楚。在一只老鼠身上 结节性硬化症模型，其中皮质神经元缺乏结节性硬化症1(TSC1)，TSC1是结节性硬化症的负调控因子 蛋白质合成的主要调节者，mTOR(雷帕霉素的哺乳动物靶标)，显著延迟了 观察髓鞘形成情况。此外，兴奋状态下mTOR的另一个负调控因子TSC2的丢失 神经元影响星形胶质细胞的发育。这些研究表明，mTOR通过神经元缺失而激活 TSC1或TSC2影响神经胶质细胞的发育，包括少突胶质细胞和星形胶质细胞。与…达成一致 这些研究，我们在外周神经系统的初步结果表明，在缺乏TSC2的小鼠中， 感觉神经元，Remak束是杂乱无章的：Remak束形状奇怪， 轴突直径异常大，每束轴突较少。我们还注意到周围有更厚的髓鞘 一些轴突和失去轴突-雪旺细胞接触的证据。这些结果表明，TSC2的缺失和 感觉神经元中mTOR的激活产生了破坏雪旺细胞的异常信号 开发和/或维护，对Remak捆绑包有显著影响。我们的目标是了解 神经元mTOR信号影响雪旺细胞和Remak束的分子机制 组织。在目标1中，我们将扩展并彻底定义TSC2缺失在感觉上的后果 神经元对雪旺细胞发育和周围神经功能的影响。在目标2中，我们将使用Genetic和Next 识别神经诱导的潜在分子机制的生成测序方法 雪旺细胞缺陷。这些研究将有助于阐明轴突衍生信号在Remak Schwann中的作用 细胞发育，并可能发现治疗周围神经病的新治疗途径。