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

基本信息

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
项目类别：
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

项目摘要

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是髓磷脂的破坏对正常神经功能至关重要，会导致许多神经系统疾病，包括腓骨肌萎缩症和许多其他周围神经病异常雪旺细胞生理学。导致轴突变性，表明神经胶质衍生的信号是轴突完整性所必需的。周围神经中的有髓鞘雪旺细胞（称为雷马克雪旺细胞）包围并包裹着小直径轴突转化为“Remak 束”，并且 Remak 束中的结构缺陷被证明是因此，雪旺细胞与轴突的相互作用对于正常的神经功能至关重要，但是小鼠中神经元对雷马克雪旺细胞发育的贡献程度尚不清楚。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)，这是蛋白质合成的主要调节因子，mTOR（哺乳动物雷帕霉素靶标），显着延迟此外，在兴奋性状态下观察到髓鞘形成的丧失，Tsc2（mTOR 的另一个负调节因子）。这些研究表明，mTOR 的激活是通过神经元缺失来实现的。 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。这些研究中，我们在周围神经系统中的初步结果表明，在缺乏 Tsc2 的小鼠中感觉神经元，Remak 束杂乱无章：Remak 束形状奇特且有附体我们还注意到轴突直径异常大，并且每束轴突较少。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 缺失和感觉神经元中 mTOR 的激活产生异常信号，破坏雪旺细胞开发和/或维护，对 Remak 捆绑包有显着影响。我们的目标是了解神经 mTOR 信号传导影响雪旺细胞和 Remak 束的分子机制在目标 1 中，我们将扩展并彻底定义 Tsc2 缺失在感觉方面的后果。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，我们将使用遗传和下一步。世代测序方法来识别神经诱导的分子机制这些研究将有助于阐明 Remac Schwann 中轴突衍生信号的作用。细胞发育并可能发现治疗周围神经病的新治疗途径。