Schwann Cell Control of Chronic Nerve Injury

描述(申请人提供)：每年，数以百万计的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。这些周围神经病的发病率相当高，继而出现疼痛、感觉改变和肌肉萎缩的症状，因为治疗选择非常有限。作为一名专门研究周围神经功能障碍的整形外科医生，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本知识，并找到将这些科学发现转化为临床护理的方法。因此，这个项目建立在我们之前工作的基础上，定义了涉及计算机控制损伤发病机制的潜在分子途径。在此之前，我们建立了一种数控损伤的实验模型，在损伤的早期阶段，雪旺细胞大量增殖并伴有脱髓鞘，但没有轴突变性。有趣的是，这似乎发生在没有炎性细胞激活的情况下。需要额外的工作来指定触发这一系列事件的信号。在这个项目中，我们将检验我们的初步假设，即电脑控制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)来激活次级信使系统，从而介导CNC损伤的机械和缺血效应。第二种假说认为，整合素作为细胞外信号转导到细胞内分子通路的关键媒介；可能的信号包括机械应激和缺血独立或协同作用。本项目的具体目的是：(1)确定电脑控制损伤是否通过改变雪旺细胞基底膜的成分来诱导纤维增殖反应；(2)测试雪旺细胞整合素是否通过与细胞外基质的功能连接来调节电脑控制损伤后的机械转导；(3)确定缺血是否通过降低机械诱导的脱髓鞘阈值来调节雪旺细胞的机械转导。本申请试图使用我们的计算机控制损伤的实验模型来定义改变细胞外基质并触发损伤相关反应的信号。在实现这些目标的过程中，我们将有可能通过针对这些特定的途径来设计新的治疗方法。 与公共卫生相关：数百万美国人患有慢性神经压迫(CNC)损伤，如腕管综合征、肘管综合征和脊神经根狭窄。在过去的八年里，我们的研究首次描述了CNC损伤是一种独特的实体，其特征是髓鞘丢失而不是轴突损伤，雪旺细胞增殖和缺乏炎症。这项应用的目标是在我们之前研究的基础上，希望确定疾病过程中涉及的关键分子途径，以便我们有可能通过针对这些特定途径来设计新的治疗方法。

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.