TRANSDUCTION OF CHRONIC NERVE INJURY BY SCHWANN CELLS

描述（改编自申请人的摘要）：外周神经功能 当神经受到持续的机械刺激时， 穿过一个潜在的受限空间基于位置和 这种机械刺激的强度，慢性神经损伤（CNI）将 表现出不同的体征和症状一些更常见的 区域包括腕管、肘管和脊神经根管。 这些病理条件影响数百万人，因为他们是有限的 疼痛和功能的丧失后 患者保守治疗失败，手术干预涉及 执行受限空间的机械减压。然而，外科手术 减压在恢复功能和消除疼痛方面往往无效。 手术治疗减轻了一些症状，应该停止 病理过程的进展。但根据时间的长短， 持续机械刺激的严重程度， 周围神经可能无法通过手术治疗逆转。所有细胞 周围神经内的类型最终受到CNI的影响。作为变更 轴突数量和功能的变化是CNI的最后事件之一， 与Wallerian变性形成对比，Wallerian变性中轴突完整性的丧失导致 一连串的事件随着CNI，雪旺细胞数量减少，成纤维细胞 增殖并增加I型胶原蛋白表达，最终轴突 数量和功能减少。该项目的重点是更好地 描述对周围神经的持续机械刺激是如何 在动物模型中转化为病理生理反应。中央 这个项目的假设是CNI启动了一系列事件， 许旺细胞死亡，许旺细胞的损失会产生一种 神经轴突的生存环境。我们计划：1）确定是否 与CNI相关的组织病理学变化在地理上与 损伤部位的定量形态学分析， 外周神经，以确定雪旺氏细胞损失的模式和时间， 成纤维细胞增殖和轴突损失; 2）为了确定是否减少 慢性神经损伤时许旺细胞数量的增加是 雪旺氏细胞凋亡; 3）确定是否缺血成分的一个 慢性神经损伤诱导一氧化氮合酶（NOS）上调 不同时期雪旺氏细胞中一氧化氮合酶的mRNA和表达 慢性神经损伤成功完成这些研究将 提供了一个更好的了解CNI的发病机制， 可以开发有效的治疗模式。

DESCRIPTION (Adapted from The Applicant's Abstract): Peripheral nerve function is compromised when there is a sustained mechanical stimulus to the nerve as it passes through a potentially constrained space. Based on the location and magnitude of this mechanical stimulus, a chronic nerve injury (CNI) will manifest with different signs and symptoms. Some of the more commonly afflicted areas include the carpal tunnel, cubital tunnel, and spinal nerve root canal. These pathologic conditions affect millions of individuals as they are limited by the pain and loss of function associated with their condition. After the patient has failed conservative treatment, surgical intervention involving a mechanical decompression of the constrained space is performed. Yet, surgical decompression is often ineffective in restoring function and eliminating pain. The surgical treatment reduces some of the symptoms and should halt the progression of the pathologic process. But based on the length of time and severity of the sustained mechanical stimulus, the histopathologic changes of the peripheral nerve may not be reversed with surgical management. All cell types within the peripheral nerve are eventually affected by CNI. As the change in axonal number and function is one of the last events in CNI, this process contrasts to Wallerian degeneration where the loss of axonal integrity leads to the cascade of events. With CNI, Schwann cells decrease in number, fibroblasts proliferate and increase type I collagen expression, and eventually axonal number and function diminish. The focus of this project is to better characterize how a sustained mechanical stimulus to a peripheral nerve is transduced into a pathophysiologic response in an animal model. The central hypothesis of this project is that CNI-initiates a cascade of events that leads to Schwann cell death, and that the loss of Schwann cells creates an inhospitable environment for axons in the nerve. We plan : 1) To determine if the histopathologic changes associated with a CNI are geographically related to the site of injury by performing quantitative morphometric analyses of the peripheral nerve to determine the pattern and timing of Schwann cell loss, fibroblast proliferation, and axonal loss; 2) To determine if the decrease in Schwann cell number that occurs with a chronic nerve injury is the result of Schwann cell apoptosis; and 3) To determine if the ischemic component of a chronic nerve injury induces an up-regulation of nitric oxide synthase (NOS) mRNA and the expression of the NOS enzyme in Schwann cells at different stages of the chronic nerve injury. Successful completion of these studies will provide a greater understanding of the pathogenesis of CNI so that more effective treatment modalities may be developed.