Developing Novel Models for Assessing Fundamental Mechanisms of Neuroma

神经瘤是由于截肢或其他神经损伤而导致的神经组织痛性肿瘤。周围神经 损伤是与最常见的战场创伤类型相关的最严重的共病，以及 这些病例中的许多最终会导致痛性神经瘤的形成。这种情况通常需要 为我们的退伍军人进行额外的侵入性手术，包括切除受伤的神经以移除 神经瘤，可能会再次形成。糖尿病，这是一个慢性健康问题，是全球VAMC的优先事项 国家，是截肢的另一个常见原因。神经瘤性疼痛(或通常称为“神经性疼痛”) 截肢者群体)也是患者减少/停止使用辅助设备的主要原因之一， 包括假肢。此外，神经瘤的存在可能是一些假体和 神经接口。虽然有可用的治疗方法，但目前还没有临床护理标准 预防或治疗神经瘤，因为现有的方法不够有效。虽然 基本上，所有未修复的神经损伤都会导致神经瘤，并不是所有的神经瘤都是痛苦的。不幸的是，在那里 对于神经瘤来说，没有“安全之窗”--疼痛可以在神经损伤后的任何时候开始，而神经损伤导致了 神经瘤。神经瘤继续生长，其结构随着时间的推移而演变，可能会引入 不会出现在正常组织和正在形成的新特性中。这些病因表明， 尽管感觉神经元是神经瘤疼痛所必需的，但神经瘤结构本身可能会确立 导致疼痛的肉体关系。因此，了解是什么因素控制了 神经瘤的结构对于开发预防神经瘤形成的方法是必要的。 我们的计划，将在随后的功绩申请中进行，将测试它是再生的假设 损伤的轴突控制神经瘤的形成，以及随后交感神经或交感神经的异常耦合 运动神经轴突和/或带有感觉轴突的免疫细胞是导致神经瘤疼痛的主要因素。为此，这 SPIRE提案旨在验证遗传模型和实验设计，使我们和现场能够 解决仍未得到解答的根本问题。这个项目将测试一组细胞类型的效用- 用于神经瘤研究的特定基因敲除和报告小鼠。提议的鼠标线的前提是 神经瘤的形成显然是通过全局敲除轴突所需的基因来完全防止的 再生。新实验设计的前提是没有现有的动物模型反映临床 神经瘤切除和复发导致的反复神经损伤的现实，尽管事实是 反复损伤的情况会引起不同于单次损伤的变化。这个尖顶项目将 提供动物线条、可视化方法和对功绩项目至关重要的初步数据，以确定 机制和试验治疗。

Neuromas are painful tumors of nerve tissue that result from amputation or other nerve injury. Peripheral nerve injury is the most-impactful comorbidity associated with the most common types of battlefield trauma, and many of these cases eventually result in formation of a painful neuroma. This condition often requires additional invasive surgery for our Veterans, including resectioning of the injured nerve to remove the neuroma, which may form again. Diabetes, a chronic health problem that is a priority for VAMCs across the country, is another common cause of amputation. Neuroma pain (or “nerve pain” as it is commonly called in the amputee community) is also one of the major reasons patients reduce/stop use of assistive devices, including prosthetics. Further, presence of neuroma can be a disqualifying factor for some prosthetics and nerve interfaces. Although treatments are available, there is currently no clinical Standard of Care for prevention or treatment of neuroma because the available approaches are not sufficiently effective. Although essentially all unrepaired nerve injuries result in a neuroma, not all neuromas are painful. Unfortunately, there is no “safe window” for neuromas – pain can begin at any point after the nerve injury which induced the neuroma. Neuromas continue to grow and their structure evolves over time, likely introducing interactions that would not occur in normal tissue and developing emergent properties. These etiological factors suggest that, although sensory neurons are necessary for neuroma pain, it is the neuroma structure itself that may establish the physical relationships which lead to pain. Therefore, understanding what factors control formation of neuroma structure is necessary to develop approaches to prevent neuroma formation. Our plan, to be pursued in subsequent MERIT applications, will tests the hypothesis that it is regeneration of injured axons which controls neuroma formation, and that subsequent aberrant coupling of sympathetic or motor axons and/or immune cells with sensory axons is the major factor driving neuroma pain. To this end, this SPiRE proposal is designed to validate genetic models and experimental designs to enable us, and the field, to address fundamental questions which remain unanswered. This project will test the utility of a set of cell type- specific knockout and reporter mice for neuroma research. The premise for the proposed mouse lines is that neuroma formation is apparently completely prevented by global knockout of a gene required for axonal regeneration. The premise for the new experimental design is that no existing animal models reflect the clinical reality of the repeated nerve injury that occurs with neuroma resection and recurrence, despite the fact that the condition of repeated injury induces changes that differ from that of single injuries. This SPiRE project will provide the animal lines, visualization methods, and preliminary data vital for MERIT projects to determine mechanisms and test treatments.