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

BCCMA：针对骨关节炎疼痛和进展：通过刺激迷走神经来减轻骨关节炎疼痛和进展的临床前 OA 模型

• 批准号: 10485419
• 负责人: Mary Beth Humphrey
• 金额: --
• 依托单位: OKLAHOMA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-10-01 至 2026-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10485419
• 关键词: Acetylcholine; Acute; Acute Pain; Address; Age; Animal Model; Ankylosing spondylitis; Anti-Inflammatory Agents; Antiinflammatory Effect; Arthralgia; Automobile Driving; Biological Markers; Bone Marrow; Bone Spur; Cartilage; Cells; Choline O-Acetyltransferase; Cholinergic Fibers; Chondrocytes; Chronic; Clinical; Clinical Data; Clinical Trials; Cytometry; Data; Degenerative polyarthritis; Development; Disease; Disease Pathway; Early treatment; Environment; Epilepsy; FDA approved; Gene Expression; Goals; Hand; Health; Healthcare Systems; Heterogeneity; Histologic; Human; Image; Immune; Immunophenotyping; Inflammation; Inflammatory; Joints; Macrophage; Measures; Mechanics; Medial meniscus structure; Mediating; Mediator; Meniscus structure of joint; Mental Depression; Modeling; Molecular; Molecular Disease; Mus; Nerve; Nerve Growth Factors; Neuroglia; Neurons; Neurotrophic Tyrosine Kinase Receptor Type 1; Nociception; Operative Surgical Procedures; Outcome; Pain; Parasympathetic Nervous System; Pathogenesis; Pathology; Pathway interactions; Patient Selection; Periosteum; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phenotype; Pilot Projects; Pre-Clinical Model; Production; Proteins; Psoriatic Arthritis; Reporter; Research; Rheumatoid Arthritis; Sampling; Serum; Signal Transduction; Spleen; Stem Cell Factor; Stratification; Synovial Membrane; Synovial joint; Synovitis; System; T-Lymphocyte; Testing; Time; Traumatic Arthropathy; Treatment Efficacy; Veterans; Weight-Bearing state; Work; alpha-bungarotoxin receptor; bench to bedside; biomarker identification; bone; burden of illness; cholinergic; chronic pain; cohort; cytokine; disability; fibromyalgia pain; improved; inhibitor; joint injury; joint loading; mast cell; meniscus injury; methyllycaconitine; microCT; mouse model; multidisciplinary; new therapeutic target; novel therapeutic intervention; osteoarthritis pain; pain reduction; patient subsets; pre-clinical; predictive marker; prevent; primary endpoint; programs; protein expression; radiological imaging; response; secondary endpoint; spontaneous pain; substantia spongiosa; systemic inflammatory response; targeted treatment

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.

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