Developing Novel Models for Assessing Fundamental Mechanisms of Neuroma

开发评估神经瘤基本机制的新模型

• 批准号: 10507778
• 负责人: Jeffrey C Petruska
• 金额: --
• 依托单位: LOUISVILLE VA MEDICAL MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-10-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10507778
• 关键词: Address; Afferent Neurons; Amputation; Amputees; Animal Model; Animals; Automobile Driving; Axon; Basic Science; Biological; Biological Factors; Biological Models; Breeding; Cell Proliferation; Cells; Chronic; Clinical; Communities; Country; Coupling; Data; Dependence; Development; Devices; Diabetes Mellitus; Disease; Etiology; Excision; Experimental Designs; Future; Genes; Genetic Models; Goals; Growth; Health; Image; Immune; Injury; Investigation; Knock-out; Knockout Mice; Local Anesthetics; Methods; Modeling; Motor; Mus; Natural regeneration; Nerve; Nerve Pain; Nerve Tissue; Neuroma; Neurons; Normal tissue morphology; Operative Surgical Procedures; Pain; Patients; Peripheral; Peripheral nerve injury; Pharmacogenetics; Physical Rehabilitation; Physical therapy; Population; Prevention; Preventive therapy; Property; Prosthesis; Proteins; Quality of life; Recurrence; Rehabilitation therapy; Reporter; Research; Resources; Schwann Cells; Self-Help Devices; Sensory; Signal Transduction; Structure; Study models; Testing; Therapeutic; Time; Transgenic Mice; Trauma; Validation; Veterans; Visualization; Work; activating transcription factor 3; axon injury; axon regeneration; cell type; comorbidity; design; experimental study; improved; improved outcome; innovation; knockout gene; loss of function; model design; motor axon regeneration; nerve injury; novel; optogenetics; prevent; recruit; regenerative; response; standard of care; therapy design; therapy development; three dimensional structure; tool; translational approach; tumor

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.

神经瘤是神经组织的疼痛性肿瘤，由放大或其他周围神经损伤引起。 损伤是与最常见的战场创伤类型相关的最具影响力的合并症，并且 许多此类病例最终会导致疼痛性神经瘤的形成。这种情况通常需要治疗。 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去除 神经瘤，它可能会再次形成，这是一种慢性健康问题，是整个 VAMC 的首要任务。 国家，是截肢疼痛（或通常称为“神经疼痛”）的另一个常见原因。 截肢者群体）也是患者减少/停止使用辅助器具的主要原因之一， 此外，神经瘤的存在可能是某些假肢的不合格因素。 尽管有治疗方法，但目前尚无临床护理标准。 预防或治疗神经瘤，因为现有的方法不够有效。 基本上所有未修复的神经损伤都会导致神经瘤，但不幸的是，并非所有神经瘤都会疼痛。 对于神经瘤来说，没有“安全窗口”——疼痛可能在神经损伤后的任何时候开始，从而诱发神经瘤 神经瘤不断生长，其结构随着时间的推移而演变，可能会引入相互作用 不会发生在正常组织中并发展出新的特性，这些病因因素表明， 尽管感觉神经元对于神经瘤疼痛是必需的，但神经瘤结构本身可能会产生疼痛 因此，了解哪些因素控制着疼痛的形成。 神经瘤结构对于开发预防神经瘤形成的方法是必要的。 我们的计划将在后续的 MERIT 应用中实施，将检验以下假设： 控制神经瘤形成的受损轴突，以及随后的交感神经或交感神经的异常耦合 运动轴突和/或具有感觉轴突的免疫细胞是驱动神经瘤疼痛的主要因素。 SPiRE 提案旨在验证遗传模型和实验设计，使我们和该领域能够 解决尚未解答的基本问题。该项目将测试一组细胞类型的实用性。 用于神经瘤研究的特异性敲除小鼠和报告小鼠 所提出的小鼠品系的前提是： 轴突所需基因的整体敲除显然可以完全阻止神经瘤的形成 新实验设计的前提是现有的动物模型没有反映临床情况。 神经瘤切除和复发时发生的反复神经损伤的现实，尽管事实是 重复损伤的情况会引起与单次损伤不同的变化。 提供对 MERIT 项目至关重要的动物品系、可视化方法和初步数据，以确定 机制和测试治疗。