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

项目摘要 关节炎影响近6000万成年美国人，发病率正在增加，骨关节炎（OA）是最常见的关节炎。 最常见的关节炎。OA是由于包括关节的组织的退化而发生的，并且与关节炎相关。 带着痛苦OA疼痛是社会慢性疼痛负担的主要贡献者。约80%的OA患者 行动受限，25%的人无法进行日常生活的主要活动。当前治疗选择 仅限于类固醇注射剂、非甾体抗炎药（NSAIDS）、阿片类药物和非甾体类药物。 药理学方法（运动，减肥）。不幸的是，这些治疗方法中的每一种都 有问题锻炼有助于体重管理，但由于持续疼痛，患者很难进行锻炼。nsaid可 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 与成瘾和滥用有关（实际上会加重慢性疼痛）。显然，我们迫切需要 为患有OA疼痛的个体鉴定新的治疗靶点和/或治疗。这里我们 提出一个迄今未被认识的神经通路是OA疼痛的关键组成部分。这条途径涉及 ARTN、其受体GFRα3和神经上的“疼痛”通道（瞬时受体电位[TRP]通道）。 该通路的激活启动并维持OA疼痛。中心假设（基于 多个物种[小鼠、狗、猫、人]）是ARTN，从OA关节的滑膜释放，以响应 损伤，导致局部和远端感觉神经中其受体GFRα3重新增加， 以及通过原癌基因酪氨酸蛋白激酶受体（RET）介导的广泛疼痛和超敏反应 多个下游TRP受体的上调。在本提案中，我们将使用多种OA模型， 临床相关的结果指标，并利用我们对自然发生OA的狗的独特访问， 目的1：为了检验ARTN表达在OA中增加并且在OA中表达增加的假设， 负责疼痛。目的2：验证ARTN/GFRα3信号通路负责行为学的假设。 在早期和晚期疾病中均表现出OA疼痛。目的3：检验RET依赖性 ARTN/GFRα3信号转导导致多个TRP通道表达和激活的变化。目标4： 测试/验证上述关键分子在天然存在的大动物模型中的参与， OA（犬）。总之，这将是首次研究ARTN/GFRα3/TRP通道的作用和机制 在OA疼痛和敏感性方面。基于可靠的临床相关初步数据，并利用来自 两个不同的和互补的学科，成功完成这项拟议的工作有可能 确定临床相关的神经机制，从而开发新的，有效的治疗方法， 治疗人类OA疼痛。

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.