Subsynovial Connective Tissue and Carpal Tunnel Syndrome

描述(由申请人提供)：腕管综合征(CTS)是美国最常见的与工作相关的残疾原因之一。CTS最常见的病理表现是非炎性纤维化和滑膜下结缔组织增厚(SSCT)，但这种纤维化是否是CTS的原因或仅仅是相关发现尚不清楚。这项研究将通过在动物模型中研究SSCT与腕管综合征的关系来解决这一重要问题。我们选择的模型是基于增殖性治疗的概念，或前驱治疗，一种通过注射增殖剂溶液诱导细胞增殖和纤维化，从而愈合的治疗方法。我们有初步证据表明，一次向兔腕管内注射10%葡萄糖可以在SSCT中诱导非常类似于CTS患者的非炎性增殖反应，最终导致正中神经脱髓鞘的发展。在这一竞争性更新中，我们建议验证这一兔模型，特别是测试模型中SSCT损伤导致纤维化进展、材料特性改变和腕管内压力增加导致正中神经病变的假设，与CTS患者中看到的类似。为了验证这一假说，我们提出了四个具体目标：比较我们的动物模型和CTS患者的材料特性和腕管压力的变化；比较我们的动物模型和CTS患者SSCT的组织学、免疫组织化学和超微结构；比较我们的动物模型和CTS患者正中神经(以及仅在动物中的神经组织学)电诊断变化的演变；以及比较高、低和顺序注射葡萄糖对我们的兔模型SSCT纤维化和正中神经病演变的有效性。如果这些目标实现，我们的假设得到支持，那么我们将第一次拥有一个模拟CTS临床演变的有效动物模型。该模型将使我们能够研究旨在阻止或逆转SSCT纤维化演变的干预措施，从而阻止或逆转CTS的发展。该模型还将使我们能够更详细地研究CTS的发病机制。

DESCRIPTION (provided by applicant): Carpal tunnel syndrome (CTS) is one of the most common causes of work-related disability in the US. The most common pathological finding in CTS is non-inflammatory fibrosis and thickening of the subsynovial connective tissue (SSCT), but whether this fibrosis is a cause of or merely an associated finding in CTS is unknown. This study will address this important issue by investigating the relationship of the SSCT to carpal tunnel syndrome in an animal model. The model that we have selected is based on the concept of proliferative therapy, or prolotherapy, a treatment that induces cellular proliferation and fibrosis, and, thus, healing, by injection of a proliferant solution. We have preliminary evidence that a single injection of 10% dextrose into the rabbit carpal tunnel can induce a non-inflammatory proliferative response in the SSCT very similar to that seen in patients with CTS, culminating eventually in the development of demyelination of the median nerve. In this competitive renewal, we propose to validate this rabbit model, specifically to test the hypothesis that damage to the SSCT in the model results in a progression of fibrosis, altered material properties and increased pressure in the carpal tunnel leading to median neuropathy, similar to that seen in CTS patients. To test this hypothesis, we propose four specific aims: to compare the changes in material properties and carpal tunnel pressure in our animal model with those seen in CTS patients; to compare the histology, immunohistochemistry and ultrastructure of the SSCT in our animal model and CTS patients; to compare the evolution of electrodiagnostic changes in the median nerve (and nerve histology in animals only) in our animal model and CTS patients; and to compare the effectiveness of higher, lower, and sequential dextrose injections on the evolution of SSCT fibrosis and median neuropathy in our rabbit model. If these aims are achieved, and our hypothesis is supported, then for the first time we will have a validated animal model which mimics the clinical evolution of CTS. This model would allow us to study interventions directed at halting or reversing the evolution of SSCT fibrosis, and thereby the development of CTS. The model would also allow us to study the pathogenesis of CTS in more detail.