Schwann Cell Control of Chronic Nerve Injury

描述（由申请人提供）：每年，数百万美国人遭受慢性神经压迫（CNC）损伤，如腕管综合征、肘管综合征和脊神经根狭窄。由于治疗选择非常有限，这些周围神经病变的发病率很高，继发于疼痛、感觉改变和肌肉萎缩等症状。作为一名专门研究周围神经功能障碍的骨科医生，作为一名内科科学家，我的目标是提高我们对潜在病理生理学的基础知识，并确定将这些科学发现转化为临床护理的方法。因此，该项目建立在我们之前的工作基础上，定义了CNC损伤发病机制中涉及的潜在分子途径。之前，我们建立了一个CNC损伤的实验模型，该模型显示在损伤早期，大量的雪旺细胞增殖伴随着脱髓鞘，没有轴突变性。有趣的是，这似乎发生在没有炎症细胞激活的情况下。需要额外的工作来指定触发事件级联的信号。在这个项目中，我们将验证我们的主要假设，即CNC损伤是一种获得性基底板相关疾病。我们将研究雪旺细胞是否通过改变细胞外基质（ECM）激活次级信使系统来介导CNC损伤的机械和缺血效应。第二种假设是，整合素是CNC损伤的细胞外信号转导到细胞内分子途径的关键中介；可能的信号包括机械应力和缺血单独或协同作用。该项目的具体目的是：(1)确定CNC损伤是否通过改变雪旺细胞基层成分诱导纤维增殖反应；(2)测试雪旺细胞整合素是否通过与ECM的功能联系成为CNC损伤后机械转导的关键调节因子；(3)确定缺血是否通过降低机械诱导脱髓鞘的阈值来调节雪旺细胞的机械转导。目前的应用旨在定义改变ECM并触发损伤相关反应的信号，使用我们的CNC损伤实验模型。在实现这些目标的过程中，我们将有潜力通过针对这些特定途径设计新的治疗方法。

DESCRIPTION (provided by applicant): Each year, millions of Americans suffer from chronic nerve compression (CNC) injuries such as carpal tunnel syndrome, cubital tunnel syndrome, and spinal nerve root stenosis. These peripheral neuropathies produce substantial morbidity secondary to symptoms of pain, altered sensation, and muscle atrophy because treatment options are very limited. As an orthopaedic surgeon specializing in peripheral nerve dysfunction, my goals as a physician-scientist are to improve our basic knowledge of the underlying pathophysiology and to identify approaches for translating these scientific discoveries into clinical care. As such, this project builds upon our prior work in defining the underlying molecular pathways involved in the pathogenesis of CNC injury. Previously, we established an experimental model for CNC injuries that demonstrated massive Schwann cell proliferation accompanied by demyelination without axonal degeneration in the early injury phase. Interestingly, this appears to occur in the absence of inflammatory cell activation. Additional work is needed to specify the signals triggering this cascade of events. In this project, we will test our primary hypothesis that CNC injury is an acquired basal lamina-associated disease. We will examine whether Schwann cells mediate the mechanical and ischemic effects of CNC injury by activating secondary messenger systems via alteration of the extracellular matrix (ECM) CM). A secondary hypothesis is that integrins serve as the critical intermediaries for the transduction of extracellular signals from CNC injury into intracellular molecular pathways; possible signals include mechanical stress and ischemia contributing independently or synergistically. The specific aims of this project are (1) to determine if CNC injury induces the fibroproliferative response by altering Schwann cell basal lamina constituents (2) to test if Schwann cell integrins are key regulators of mechanotransduction after CNC injury via functional linkage to the ECM, and (3) to determine whether ischemia modulates Schwann cell mechanotransduction by lowering the threshold for mechanically induced demyelination. The present application seeks to define the signals that alter the ECM and trigger the injury-related responses, using our experimental models of CNC injury. In accomplishing these goals, we will have the potential to design novel new therapies by targeting these specific pathways. PUBLIC HEALTH RELEVANCE: Millions of Americans suffer from chronic nerve compression (CNC) injuries such as carpal tunnel syndrome, cubital tunnel syndrome and spinal nerve root stenosis. Over the past eight years our research described for the first time that CNC injuries are a distinct entity characterized by the loss of myelin without axonal injury, the proliferation of Schwann cells and a lack of inflammation. The goal of this application is to build upon our previous research in the hopes of identifying the key molecular pathways involved in the disease process so that we will have the potential to design novel new therapies by targeting these specific pathways.