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.

神经瘤是由截肢或其他神经损伤引起的神经组织的疼痛性肿瘤。周围神经 损伤是与最常见类型的战场创伤相关的最具影响力的合并症， 这些病例中的许多最终导致疼痛性神经瘤的形成。这种情况往往需要 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， 神经瘤，可能会再次形成。糖尿病是一种慢性健康问题，是全世界VAMC的优先事项。 这是另一个常见的截肢原因。神经瘤疼痛（或“神经疼痛”，因为它通常被称为在 截肢者群体）也是患者减少/停止使用辅助装置的主要原因之一， 包括假肢此外，神经瘤的存在可能是一些假体的不合格因素， 神经接口虽然治疗是可用的，但目前没有临床护理标准。 预防或治疗神经瘤，因为可用的方法不够有效。虽然 基本上所有未修复的神经损伤都会导致神经瘤，但并非所有神经瘤都是疼痛的。可惜 对于神经瘤来说，没有“安全窗口”-疼痛可以在神经损伤后的任何时候开始， 神经瘤神经瘤继续生长，它们的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。这些病因学因素表明， 虽然感觉神经元是神经瘤疼痛所必需的，但是神经瘤结构本身可以建立 导致疼痛的身体关系。因此，了解哪些因素控制着 神经瘤结构是开发预防神经瘤形成的方法所必需的。 我们的计划，将在随后的MERIT应用程序中进行，将测试它是再生的假设。 控制神经瘤形成的受损轴突，以及随后的交感神经或 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。为此，这 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 解决尚未解决的根本问题。该项目将测试一组细胞类型的效用- 用于神经瘤研究的特异性敲除和报告小鼠。建议的鼠标线的前提是， 神经瘤的形成显然是完全防止了轴突生长所需的基因的整体敲除， 再生新实验设计的前提是现有的动物模型不能反映临床 神经瘤切除术和复发时发生的反复神经损伤的现实，尽管事实上， 重复损伤的情况引起不同于单次损伤的变化。SPiRE项目将 提供动物线，可视化方法和初步数据，这些数据对MERIT项目至关重要， 机制和测试治疗。