BCCMA: Targeting Osteoarthritis Pain and Progression: Preclinical OA models of vagal nerve stimulation to reduce pain and progression of OA

项目概要： OA是我们的退伍军人慢性疼痛和残疾的主要原因，他们在明显年轻的时候就患上了OA。 年龄和人数高于非退伍军人。因此，OA的疾病负担不成比例 由退伍军人和VA医疗保健系统（VAHCS）承担。目前还没有疾病修饰抗- 骨关节炎药物（DMOAD），部分原因是历史上重点关注放射学OA的识别和跟踪 结果，而不是疼痛和功能相关的疾病途径。我们的综合研究计划在治疗 骨关节炎疼痛和进展（TOPP）协作绩效计划将检验中心假设， OA疼痛和结构进展的变异性与细胞和分子的异质性有关， 骨、软骨和滑膜对炎症和关节负荷的反应。这一合作成果将 追求两个首要的具体目标：目标1：提高对骨关节炎（OA）发病机制的理解， 目标2：建立新的靶向治疗方法的临床前数据 治疗目标是减轻疼痛和预防OA进展。使用早期和晚期OA临床队列 在VAHCS和关节损伤动物模型中普遍存在以测试新的治疗方法将需要 协调的多学科工作台到床边工作，没有一个单一的项目可以充分解决。此外，本发明还 我们将结合迷走神经刺激（VNS）治疗效果的结果，靶向神经生长因子， (NGF)，并在临床前OA动物模型中靶向肥大细胞，具有人OA表型和分层 将允许快速过渡到OA和关节损伤的临床试验。项目4的目标是确定 经皮迷走神经刺激（tVNS）可减轻疼痛并防止结构性进展 急性和慢性临床前OA模型。VNS，目前FDA批准用于癫痫和抑郁症， 激活胆碱能抗炎通路，驱动神经和非神经系统中乙酰胆碱（Ach）的产生。 神经元细胞，并提供强的全身抗炎作用，减少滑膜炎症， 类风湿性关节炎小鼠模型的关节疼痛。在关节内，胆碱能纤维支配滑膜， 骨小梁和骨膜，研究表明副交感神经系统调节 伤害性疼痛和可能的OA发病机制。巨噬细胞中的烟碱乙酰胆碱受体α 7（α 7NAChR）， T细胞和软骨细胞可能介导VNS效应。基于这些和我们令人兴奋的初步数据， 在不稳定的内侧半月板损伤模型中，经过4周的VNS治疗后，疼痛得到改善，我们的假设是， 减轻疼痛并防止OA的结构性进展。我们将从三个方面来检验这一假设：（1）检验是否 tVNS减轻OA的急性和慢性小鼠模型中的疼痛，（2）测试tVNS是否减缓OA的结构进展。 OA的急性和慢性小鼠模型，和（3）整合OA动物模型中tVNS的结果与人类 OA表型分析，以确定预测VNS反应或OA进展的生物标志物。结果将有一个 通过提供VNS改善疼痛的关键临床前证据， 预防OA进展，并将提供重要的人类生物标志物，以改善对患有 早期或晚期OA，用于VNS和其他新兴治疗的临床试验。

Project Summary: OA is a leading cause of chronic pain and disability in our Veterans who develop OA at significantly younger ages and in higher numbers than non-Veterans. Consequently, the disease burden of OA is disproportionately borne by Veterans and the VA Healthcare system (VAHCS). Currently there are no disease modifying anti- osteoarthritis drugs (DMOAD) due in part to a historical focus on identification and tracking of radiographic OA outcomes rather than pain and function-related disease pathways. Our integrated research program in the Treat Osteoarthritis Pain and Progression (TOPP) Collaborative Merit program will test the central hypothesis that variability in OA pain and structural progression is related to heterogeneity in the cellular and molecular responses of bone, cartilage, and synovium to inflammation and joint loading. This Collaborative Merit will pursue two overarching Specific Aims: Aim 1: To improve understanding of osteoarthritis (OA) pathogeneses to enable development of targeted therapeutic approaches, and Aim 2: To establish preclinical data for new therapeutic targets to reduce pain and prevent OA progression. Using early and late OA clinical cohorts prevalent in the VAHCS and joint injury animal models to test novel therapeutic approaches will require coordinated multidisciplinary bench to bedside work for that no single project can adequately address. Further, we will couple results from treatment efficacy of vagal nerve stimulation (VNS), targeting nerve growth factor (NGF), and targeting mast cells in preclinical OA animal models with human OA phenotyping and stratification will allow for rapid transition to clinical trials in OA and joint injury. The goal of Project 4 is to determine if transcutaneous vagal nerve stimulations (tVNS) reduces pain and prevents structural progression in acute and chronic preclinical OA models. VNS, currently FDA approved for epilepsy and depression, activates a cholingeric anti-inflammatory pathway, driving production of acetylcholine (Ach) in nerves and non- neuronal cells, and provides a strong systemic anti-inflammatory effect that reduces synovial inflammation and joint pain in mouse models of rheumatoid arthritis. Within the joint, cholinergic fibers innervate the synovium, trabecular bone, and periosteum and studies suggest that the parasympathetic nervous system modulates nociceptive pain and possibly OA pathogenesis. Nicotinic acetylcholine receptor α7 (α7NAChR) in macrophages, T cells, and chondrocytes may mediate VNS effects. Based on these and our exciting preliminary data showing improved pain after 4 weeks of VNS in the destabilized medial meniscal injury model, our hypothesis is that tVNS reduces pain and prevents structural progression in OA. We will test this hypothesis in three aims: (1) Test if tVNS reduces pain in acute and chronic mouse models of OA, (2) test if tVNS slows structural progression of acute and chronic mouse models of OA, and (3) Integrate outcomes of tVNS in OA animal models with human OA phenotyping to identify biomarkers predictive of VNS response or OA progression. Results will have a substantial impact on Veteran Health by providing critical preclinical evidence that VNS improves pain and prevents progression of OA and will provide important human biomarkers to improve selection of patients with early or late-stage OA for clinical trials of VNS and other emerging treatments.