15-LOX-1 as a druggable target in the acute to chronic pain transition of rheumatoid arthritis

15-LOX-1 作为类风湿性关节炎急性至慢性疼痛转变中的药物靶点

基本信息

批准号：
10407588
负责人：
Ann Marie Gregus
金额：
$ 34.85万
依托单位：
VIRGINIA POLYTECHNIC INST AND ST UNIV
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10407588
关键词：
ARNT gene Acute Address Affective Age Agonist Analgesics Antiepileptic Agents Anxiety Applications Grants Arachidonate 15-Lipoxygenase Arthralgia Arthritis Attenuated Autoimmune Diseases Behavior assessment Behavioral Biochemical Biological Assay Biological Products Body Temperature Buprenorphine Cells Chronic Clinical Clinical assessments Data Development Disease model Drug Targeting Enzymes Etanercept Exhibits Fc Receptor Female Glutamates Hand Strength Histocytochemistry Human Hypersensitivity Immunohistochemistry In Vitro Incidence Inflammation Inflammatory Injury Intervention K/BxN model Knock-out Leukocytes Lipids Lipopolysaccharides Maintenance Measurement Measures Mechanics Mediating Mental Depression Microglia Modeling Molecular Mus Musculoskeletal Neuroglia Neurons Neuropathy Nociception Nociceptors Non-Steroidal Anti-Inflammatory Agents Opioid Opioid agonist Orphan Pain Pathway interactions Peripheral Permeability Phase Phase Transition Population Prostaglandin-Endoperoxide Synthase Publishing Rattus Redness Reflex action Resolution Rheumatoid Arthritis Risk Rodent Rodent Model Role Sensory Serum Source Spinal Spinal Cord Spinal Ganglia Steroid therapy Steroids Swelling TLR4 gene TRPV1 gene Tactile Testing Therapeutic Up-Regulation Woman Work addiction allodynia ankle joint antagonist arthritic pain base cell type central sensitization chronic neuropathic pain chronic pain chronic pain management clinical development druggable target functional disability gabapentin insight joint inflammation macrophage male mu opioid receptors new therapeutic target non-opioid analgesic novel novel therapeutics opioid misuse pain chronification peripheral blood phase II trial prevent psychiatric comorbidity receptor response sex side effect small molecule targeted agent

项目摘要

PROJECT SUMMARY Rheumatoid arthritis (RA) is one of the most common autoimmune diseases with a 0.5-1% worldwide incidence. Current therapies including steroids, biologics and nonsteroidal anti-inflammatory drugs (NSAIDs) targeting cyclooxygenases (COX) alleviate clinical signs of inflammation; however, joint pain characterized by mechanical hypersensitivity (allodynia) and functional disabilities (grip strength deficit, locomotor depression) along with psychiatric comorbidities (anxiety, depression) often remain well beyond resolution of peripheral inflammation. Thus, there exists a critical need for new therapeutics for the management of persistent arthritic pain. In the K/BxN serum transfer model of RA, allodynia during the early inflammatory phase is attenuated by conventional therapeutics (NSAIDs, the antiepileptic gabapentin, the TNFa receptor antibody etanercept, the partial mu opioid receptor agonist buprenorphine), but is only modestly reduced by gabapentin in the late post-inflammatory phase, indicating that the pathways targeted by these agents likely do not drive the chronification of arthritic pain. Transition to the neuropathic post-inflammatory allodynia is mediated by spinal Toll-like receptor 4 (TLR4), and intrathecal (IT) delivery of the TLR4 agonist Lipopolysaccharide (LPS) to model this transition phase produces tactile allodynia and grip strength deficits (a widely utilized rheumatological measure of musculoskeletal function) in both sexes. The lipoxygenase 15-LOX-1 has emerged as a viable target in disease models, and its bioactive metabolites (12/15-lipoxygenase metabolites; 12/15-LMs) contribute to allodynia at the spinal level. Our published and preliminary data demonstrate a critical role of spinal 12/15-LMs in mechanical pain hypersensitivity in rodents: i) 12/15-LMs activate multiple targets expressed in nociceptors; ii) intrathecal (IT) LPS (TLR4 agonist) produces allodynia in rodents and increases 15-LOX-1 expression; iii) spinal or systemic inhibition of 15-LOX-1, but not of COX, abrogates TLR4-mediated allodynia in rats and mice and iv) peripheral inflammation in rats or K/BxN serum transfer arthritis in mice induces spinal synthesis of 12/15-LMs and allodynia via several receptors. Given these observations, the proposed studies herein will test the overarching hypothesis that spinal 15-LOX activation mediates the transition from acute to chronic pain during K/BxN arthritis in males and females via 3 aims by investigating 1) the role of spinal 15-LOX-1 in the acute to chronic transition of pain in K/BxN arthritis 2) the cellular source(s) of spinal 15-LOX-1 and 3) the spinal receptor-mediated nociceptive effects of 15-LOX-1 metabolites using a variety of behavioral (tactile, grip strength, open field, clinical signs of inflammation), molecular and biochemical assays. Collectively, the expected results will address significant gaps in understanding of the mechanisms underlying sensory and affective components of chronic pain and interrogate 15-LOX-1 as a novel druggable target to impede activation of multiple downstream receptors in an alternative therapeutic strategy for treating arthritic pain states persisting after resolution of inflammation.

项目概要类风湿性关节炎 (RA) 是最常见的自身免疫性疾病之一，全球发病率为 0.5-1%。目前的治疗方法包括类固醇、生物制剂和非类固醇抗炎药 (NSAID) 环氧合酶 (COX) 减轻炎症的临床症状；然而，以机械性为特征的关节疼痛过敏（异常性疼痛）和功能障碍（握力不足、运动抑制）以及精神合并症（焦虑、抑郁）常常远远超出周围炎症的解决范围。因此，迫切需要新的治疗方法来治疗持续性关节炎疼痛。在 RA 的 K/BxN 血清转移模型，早期炎症阶段的异常性疼痛通过常规方法减弱治疗药物（NSAID、抗癫痫加巴喷丁、TNFa 受体抗体依那西普、部分 mu 阿片类药物受体激动剂丁丙诺啡），但在炎症后晚期加巴喷丁仅适度减少阶段，表明这些药物所针对的途径可能不会导致关节炎疼痛的慢性化。向神经性炎症后异常性疼痛的转变是由脊髓 Toll 样受体 4 (TLR4) 介导的，并且鞘内 (IT) 递送 TLR4 激动剂脂多糖 (LPS) 来模拟这一过渡阶段，产生触觉异常性疼痛和握力缺陷（广泛使用的肌肉骨骼功能风湿病测量方法）男女皆宜。脂氧合酶 15-LOX-1 已成为疾病模型中的可行靶标，其生物活性代谢物（12/15-脂氧合酶代谢物；12/15-LM）会导致脊髓水平的异常性疼痛。我们的已发表的初步数据表明脊髓 12/15-LM 在机械性疼痛过敏中发挥关键作用在啮齿类动物中： i) 12/15-LM 激活伤害感受器中表达的多个目标； ii) 鞘内 (IT) LPS（TLR4 激动剂）在啮齿类动物中产生异常性疼痛并增加 15-LOX-1 的表达； iii) 15-LOX-1的脊髓或全身抑制，但不是 COX，消除大鼠和小鼠中 TLR4 介导的异常性疼痛，以及 iv) 大鼠中的外周炎症或小鼠 K/BxN 血清转移性关节炎通过多种受体诱导 12/15-LM 的脊髓合成和异常性疼痛。鉴于这些观察结果，本文提出的研究将检验脊髓 15-LOX 的总体假设激活介导男性和女性 K/BxN 关节炎期间从急性疼痛到慢性疼痛的转变，通过 3 目的是通过研究 1) 脊髓 15-LOX-1 在 K/BxN 关节炎疼痛急性向慢性转变中的作用 2) 脊髓 15-LOX-1 的细胞来源和 3) 脊髓受体介导的 15-LOX-1 伤害感受作用使用各种行为（触觉、握力、开放视野、炎症的临床症状）的代谢物，分子和生化测定。总的来说，预期结果将弥补在了解慢性疼痛的感觉和情感成分的机制并询问 15-LOX-1 作为一种新型药物靶标，可替代地阻止多个下游受体的激活治疗炎症消退后持续存在的关节炎疼痛状态的治疗策略。