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

基本信息

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
项目类别：
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

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

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项目摘要

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.

项目摘要关节炎影响了近6000万成年美国人，并且发病率正在增加，骨关节炎（OA）是关节炎的最常见形式。 OA发生是由于完成关节的组织变性，并且与痛苦。 OA疼痛是社会慢性疼痛燃烧的主要因素。大约80％的OA患者遭受运动的限制，而25％的人无法从事日常生活的重大活动。当前的治疗选择仅限于类固醇注射，非甾体抗炎药（NSAID），阿片类药物和非 - 药理方法（运动，体重减轻）。不幸的是，这些治疗方法中的每一种都是有问题的。由于持续的疼痛，锻炼对体重管理有助于体重管理。 NSAID可以导致胃肠道刺激和出血，并增加心脏病或中风的风险，而阿片类药物为与成瘾和虐待有关（实际上可能会恶化慢性疼痛）。显然，有急需为患有OA疼痛的人确定新的治疗靶标和/或治疗方法。在这里，我们提议迄今未识别的神经途径是OA疼痛的关键组成部分。该途径涉及 ARTN，其受体GFRα3和神经上的“疼痛”通道（瞬态受体电位[TRP]通道）。该途径的激活启动并保持OA疼痛。中心假设（基于初步数据多种物种[小鼠，狗，猫，人]）是Artn，从OA关节的滑膜上释放出来受伤，在局部和遥远的感觉神经中，其受体GFRα3从头增加，产生局部通过原癌基因酪氨酸 - 蛋白酶受体（RET）介导的宽度疼痛和超敏反应多个下游TRP受体的上调。在此建议中，我们将使用多个OA模型，并且临床上相关的结果指标，并利用我们自然发生的OA的独特访问狗的独特访问权限达到以下目的：目标1：检验OA中ARTN表达增加的假设，IS 负责疼痛。目标2：测试ARTN/GFRα3信号传导负责的假设在早期和晚期疾病中表现出OA疼痛。目标3：检验依赖RET的假设 ARTN/GFRα3信号传导导致多个TRP通道表达和激活的变化。目标4：到测试/验证上述键分子在天然发生的大型动物模型中的参与 OA（狗）。总体而言，这将是研究ARTN/GFRα3/TRP通道的作用和机制的第一项工作在OA疼痛和敏感性中。基于坚实的临床相关初步数据，并利用PI专业知识两个不同且完整的学科，成功完成这项拟议的工作有可能确定临床上相关的神经力学，从而开发新的有效疗法在人类中的oa pain治疗。