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Transduction of Mechanical Stimuli in Myelination and Peripheral Nerve Repair

髓鞘形成和周围神经修复中机械刺激的转导

基本信息

批准号：
10755836
负责人：
Yannick Poitelon
金额：
$ 5.38万
依托单位：
ALBANY MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-15 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10755836
关键词：
Ablation Affect Agonist Axon Cations Cell Differentiation process Cell physiology Cells Chemicals Clinical Treatment Cytoskeleton DNA-Binding Proteins Data Development Disease Economic Burden Elasticity Extracellular Matrix Fiber Funding Gene Expression Gene Expression Regulation Genes Genets Growth Health Impairment In Vitro Injury Ion Channel Knock-out Knockout Mice Mechanics Mediating Modeling Molecular Myelin Neuroglia Neuropathy Pathway interactions Peripheral Nerves Peripheral Nervous System Peripheral Nervous System Diseases Peripheral nerve injury Persons Physiologic pulse Piezo 1 ion channel Public Health Radial Regulation Research Role Schwann Cells Signal Transduction Stimulus Structure Symptoms Testing Therapeutic Therapeutic Effect Tissues Transducers Trauma Ultrasonic wave Variant axon injury design improved in vivo knock-down mechanical stimulus mechanotransduction mouse model myelination nervous system development new therapeutic target novel peripheral nerve regeneration peripheral nerve repair regeneration potential remyelination response sensor small hairpin RNA social transcription factor ultrasound

项目摘要

Mechanobiology is an emerging field which studies how physical forces and changes can contribute to cell differentiation, tissue formation and diseases. These forces are applied on cells through the local variations between neighbouring cells and the extracellular matrix. Notably, cell—cell and cell-extracellular matrix mechanical stimuli can stimulate electrochemical responses, the rearrangement of cytoskeletal structures and the regulation of gene expression. Schwann cells, the myelinating cells of the peripheral nervous system, are required for the function and health of the peripheral nervous system. Schwann cells also have a critical role in the regenerative potential of the peripheral nervous system, but very little is known about how Schwann cells sense axonal injury. We demonstrated that Schwann cells are exquisitely sensitive to alterations in the elasticity of the extracellular matrix; and that Schwann cell differentiation and myelination during the peripheral nervous system development depend on the transduction of mechanical stimuli by YAP and TAZ. Yet, it is unknown what are the signalling upstream and downstream YAP and TAZ in Schwann cells and if YAP and TAZ are also required for Schwann cell differentiation and remyelination after peripheral nerve injury. Here we will investigate if the transduction of mechanical stimuli in Schwann cells is critical to stimulate myelination and improve peripheral nerve regeneration. Our objectives are to determine if it is possible to manipulate Schwann cells mechanically to improve myelination, with therapeutic implications (Aim 3) and to discover new components of the mechanotransduction pathways upstream (Aim1) and downstream (Aim 2) of YAP and TAZ. Studying myelination through the mechanotransducers YAP and TAZ has potential to advance the field by identifying the therapeutic importance of Schwann cell and cellular mechanobiology and may reveal novel targets or mechanisms for myelin formation and peripheral nerve regeneration in neuropathies molecular.

机械生物学是一个新兴的领域，它研究物理力和变化如何有助于细胞分化、组织形成和疾病。这些力通过局部变化作用在细胞上相邻细胞和细胞外基质之间的联系。值得注意的是，细胞-细胞和细胞-胞外基质机械刺激可以刺激电化学反应，细胞骨架结构的重排，基因表达的调控。雪旺细胞，周围神经系统的髓鞘形成细胞，是神经系统功能和周围神经系统的健康。雪旺氏细胞在再生过程中也起着关键作用。神经系统的潜在的，但很少有人知道许旺细胞如何感觉轴突损伤。我们证明了雪旺细胞对血管弹性的改变非常敏感。细胞外基质;以及周围神经系统中雪旺细胞分化和髓鞘形成发育依赖于雅普和TAZ对机械刺激的转导。然而，不知道是什么。雪旺细胞中的信号上游和下游雅普和TAZ，以及是否还需要雅普和TAZ 对周围神经损伤后雪旺细胞分化和髓鞘再生的影响。在这里，我们将调查，如果在雪旺细胞的机械刺激的转导是至关重要的刺激髓鞘形成和改善周围神经再生。我们的目标是确定是否有可能机械操纵雪旺细胞以改善髓鞘形成，具有治疗意义（目的3），发现机械转导途径上游（Aim 1）和下游（Aim 2）的新组分，雅普和塔兹。通过机械转换器雅普和TAZ研究髓鞘形成具有通过鉴定许旺细胞和细胞机械生物学的治疗重要性来推进该领域的潜力，并且可以揭示新的神经生物学机制。神经病分子中髓鞘形成和周围神经再生的靶点或机制。