Evaluation of mechanistic role of artemin/GFRα3 signaling in osteoarthritis pain

artemin/GFRα3 信号在骨关节炎疼痛中的机制作用评估

• 批准号: 10444070
• 负责人: Duncan Lascelles
• 金额: $ 66.79万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10444070
• 关键词: Activities of Daily Living; Address; Adult; Affect; Afferent Neurons; American; Animal Model; Arthralgia; Arthritis; Automobile Driving; Behavioral; Behavioral Assay; Binding; Biological Products; Body Weight decreased; Canis familiaris; Chronic; Complex; Data; Degenerative polyarthritis; Development; Discipline; Disease; Distant; Economic Burden; Enzyme-Linked Immunosorbent Assay; Evaluation; Exercise; Family; Felis catus; Generations; Hemorrhage; Human; Hypersensitivity; Imaging Techniques; In Vitro; Incidence; Individual; Injections; Injury; Iodoacetates; Joints; Knockout Mice; Lead; Life Expectancy; Link; Measures; Medial meniscus structure; Mediating; Modeling; Molecular; Monoclonal Antibodies; Mus; Myocardial Infarction; Nerve; Neural Pathways; Neuronal Plasticity; Neurons; Non-Steroidal Anti-Inflammatory Agents; Obesity; Operative Surgical Procedures; Opioid; Outcome Measure; Overdose; Pain; Pain management; Pathway interactions; Patients; Persistent pain; Persons; Pharmacotherapy; Proteins; Proto-Oncogenes; Quantitative Reverse Transcriptase PCR; Receptor Protein-Tyrosine Kinases; Reflex action; Research; Risk; Role; Signal Transduction; Societies; Solid; Source; Steroids; Stroke; Synovial Membrane; TRP channel; Testing; Therapeutic; Tissues; Transgenic Mice; Up-Regulation; Weight maintenance regimen; Work; addiction; afferent nerve; base; central pain; chronic pain; clinically relevant; disability; gastrointestinal; glial cell-line derived neurotrophic factor; inhibitor; irritation; joint destruction; molecular imaging; motor impairment; mouse model; neuromechanism; neurotrophic factor; new therapeutic target; novel; opioid overdose; opioid use; osteoarthritis pain; pain relief; pain sensitivity; receptor; response to injury; side effect; therapeutic target; therapeutically effective; tissue degeneration

PROJECT SUMMARY Arthritis affects almost 60M adult Americans and is increasing in incidence, with osteoarthritis (OA) being the most common form of arthritis. OA occurs due to degeneration of tissues comprising joints, and is associated with pain. OA pain is a major contributor to the burden of chronic pain in society. About 80% of persons with OA suffer movement limitations, and 25% cannot perform major activities of daily living. Current treatment options are limited to steroid injections, nonsteroidal anti-inflammatory drugs (NSAIDS), opioids and non- pharmacological approaches (exercise, weight loss). Unfortunately, each of these therapeutic approaches are problematic. Exercise, which helps weight management, is difficult for patients due to ongoing pain. NSAIDS can cause gastrointestinal irritation and bleeding and increase risk of heart attack or stroke, and opioids are associated with addiction and abuse (and can actually worsen chronic pain). Clearly, there is a critical need to identify new therapeutic targets and/or treatments for individuals suffering from OA pain. Here, we propose that a heretofore unrecognized neural pathway is a critical component of OA pain. This pathway involves ARTN, its receptor GFRα3, and ‘pain’ channels on nerves (transient receptor potential [TRP] channels). Activation of this pathway initiates and maintains OA pain. The central hypothesis (based on preliminary data in multiple species [mouse, dog, cat, human]) is that ARTN, released from synovium of the OA joint in response to injury, results in de novo increase in its receptor, GFRα3, in local and distant sensory nerves, producing local and widespread pain and hypersensitivity via Proto-oncogene tyrosine-protein kinase receptor (RET)-mediated upregulation of multiple downstream TRP receptors. In this proposal, we will use multiple OA models and clinically relevant outcome measures, and leverage our unique access to dogs with naturally occurring OA, to achieve the following aims: Aim 1: To test the hypothesis that ARTN expression is increased in OA and is responsible for pain. Aim 2: To test the hypothesis that ARTN/GFRα3 signaling is responsible for behaviorally manifested OA pain both in early and late stage disease. Aim 3: To test the hypothesis that RET-dependent ARTN/GFRα3 signaling results in changes in multiple TRP channel expression and activation. Aim 4: To test/validate involvement of the above-described key molecules in a naturally occurring large animal model of OA (dog). Overall, this will be the first work investigating the role and mechanisms of ARTN/GFRα3/TRP channel in OA pain and sensitivity. Based on solid, clinically relevant preliminary data, and leveraging PI expertise from two different and complementary disciplines, successful completion of this proposed work has the potential to identify clinically relevant neural mechanisms leading to the development of novel, effective therapeutics for the treatment of OA-pain in humans.

项目总结 关节炎影响着近6000万美国成年人，而且发病率正在增加，其中骨关节炎(OA)是 最常见的关节炎。骨性关节炎是由于组成关节的组织退化而发生的，并与 带着痛苦。骨性关节炎疼痛是社会慢性疼痛负担的主要贡献者。约80%的骨性关节炎患者 行动受限，25%的人无法进行日常生活中的主要活动。当前的治疗方案 仅限于类固醇注射、非类固醇抗炎药(NSAID)、阿片类药物和非类固醇药物 药理学方法(运动、减肥)。不幸的是，这些治疗方法中的每一种 这是个问题。运动有助于控制体重，但由于持续的疼痛，患者很难进行锻炼。非甾体抗炎药可以 引起胃肠道刺激和出血，增加心脏病发作或中风的风险，阿片类药物是 与上瘾和虐待有关(而且实际上会加重慢性疼痛)。显然，有一种迫切的需要 为患有骨性关节炎疼痛的患者确定新的治疗目标和/或治疗方法。在这里，我们 提出到目前为止未被识别的神经通路是骨性关节炎疼痛的关键组成部分。这条途径涉及到 Artn及其受体GFRTr3和神经上的“痛”通道(瞬时受体电位α通道)。 这一通路的激活启动并维持了骨性关节炎的疼痛。中心假设(基于#年的初步数据 多种物种[老鼠、狗、猫、人])是ARTN，从OA关节的滑膜中释放出来，以响应 损伤导致其受体α3在局部和远端感觉神经中从头开始增加，从而产生局部 原癌基因酪氨酸蛋白激酶受体(RET)介导的广泛性疼痛和超敏反应 上调多个下游色氨酸受体。在本提案中，我们将使用多种办公自动化模型和 临床相关的结果测量，并利用我们独特的途径接触自然发生的骨性关节炎的狗，以 实现以下目标：目标1：验证ARTN在OA和IS中表达增加的假说 对疼痛负责。目的2：验证ARTN/GFRAR3信号与行为有关的假说 在疾病的早期和晚期均表现为骨性关节炎疼痛。目的3：检验RET依赖的假设 ARTn/GFRα-3信号转导导致多个Trp通道表达和激活的改变。目标4：实现 在自然发生的大动物模型中测试/验证上述关键分子的参与 OA(狗)。总之，这将是第一个研究ARTN/GFRα3/Trp通道的作用和机制的工作 在骨质疏松症疼痛和敏感方面。基于坚实的、临床相关的初步数据，并利用来自 两个不同和相辅相成的学科，成功完成这项拟议工作有可能 确定临床上相关的神经机制，从而开发出新的、有效的治疗方法 人类骨性关节炎疼痛的治疗。