TRANSDUCTION OF CHRONIC NERVE INJURY BY SCHWANN CELLS

描述(改编自申请者摘要)：周围神经功能 当神经受到持续的机械刺激时会受到损害 穿过一个可能受到限制的空间。根据位置和 这种机械刺激的幅度，慢性神经损伤(CNI)将 表现为不同的体征和症状。一些更常见的患者 区域包括腕管、肘管和脊神经根管。 这些病理情况影响着数百万人，因为它们是有限的。 与他们的状况相关的疼痛和功能丧失。后 患者保守治疗失败，手术干预涉及 执行受限空间的机械解压缩。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，应该会停止 病理过程的进展。但基于时间的长短和 持续机械刺激的严重程度，组织病理学改变 周围神经可能不能通过手术治疗逆转。所有单元格 周围神经内的类型最终会受到CNI的影响。随着变化的发生 在轴突数目和功能上是CNI的最后事件之一，这一过程 与沃勒变性形成对比，后者轴突完整性的丧失会导致 一连串的事件。CNI后雪旺细胞数量减少，成纤维细胞 增殖并增加I型胶原的表达，最终形成轴突 数量和功能都在减少。这个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。中环 这个项目的假设是，CNI-启动了一系列事件，导致 与雪旺细胞死亡有关，而雪旺细胞的丧失会导致 对于神经中的轴突来说，不适宜居住的环境。我们计划：1)确定是否 与CNI相关的组织病理学改变在地理上与 通过对损伤部位进行形态定量分析确定损伤部位 以确定雪旺细胞丢失的模式和时间， 成纤维细胞增殖和轴突丢失；2)确定是否减少 慢性神经损伤时出现的雪旺细胞数量是由 雪旺细胞的凋亡；以及3)确定脑缺血的成分是否 慢性神经损伤诱导一氧化氮合酶(NOS)上调 不同发育阶段雪旺细胞的基因表达及一氧化氮合酶的表达 慢性神经损伤的症状。成功完成这些研究将 加深对CNI发病机制的了解，以便更多 可以开发出有效的治疗方式。

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.