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：
10627818
负责人：
Ann Marie Gregus
金额：
$ 35.2万
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/10627818
关键词：
Acute Affective Age Agonist Analgesics Ankle 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 Disease model Drug Targeting Enzymes Etanercept Exhibits Fc Receptor Female Glutamates Hand Strength Histocytochemistry Human Hypersensitivity Immunohistochemistry In Vitro Incidence Inflammation Inflammatory Injury Intervention Joints K/BxN model Knock-out Leucocytic infiltrate Leukocytes Lipids Lipopolysaccharides Lipoxygenase Macrophage 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 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 Vertebral column Western Blotting Woman Work addiction allodynia antagonist arthritic pain cell type central sensitization chronic neuropathic pain chronic pain chronic pain management clinical development druggable target functional disability gabapentin insight joint inflammation 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.

项目摘要类风湿关节炎（RA）是最常见的自身免疫性疾病之一，全球发病率为0.5-1％。当前疗法包括类固醇，生物制剂和非甾体类抗炎药（NSAIDS）靶向环氧酶（COX）减轻炎症的临床体征；但是，以机械为特征的关节疼痛高敏性（异常性疾病）和功能障碍（抓地力不足，运动抑制）以及精神病合并症（焦虑，抑郁）通常远远超出了外周炎症的解决方案。因此，存在对持续性关节炎疼痛的管理新治疗学的迫切需求。在 RA的K/BXN血清转移模型，早期炎症阶段的异常性疾病被常规治疗剂（NSAIDS，抗癫痫Gabapentin，TNFA受体抗体依然酸盐，部分MU阿片类药物受体激动剂丁丙诺啡），但仅在炎症后晚期被加巴喷丁降低阶段，表明这些药物靶向的途径可能不会驱动关节炎的编年期。过渡到神经性炎性后异常性异常症是由脊柱收费受体4（TLR4）介导的，而 TLR4激动剂脂多糖（LPS）的鞘内（IT）递送以建模该过渡阶段产生触觉异常症和抓地力缺陷（一种广泛使用的肌肉骨骼功能的流变学测量）在两个性别中。脂氧合酶15-LOX-1已成为疾病模型中的可行靶标，其生物活性代谢产物（12/15-脂氧酶代谢产物； 12/15-LMS）在脊柱水平上有助于异肌。我们的已发布和初步数据证明了脊柱12/15-LM在机械疼痛超敏反应中的关键作用在啮齿动物中：i）12/15-lms激活在伤害感受器中表达的多个靶标； ii）鞘内（IT）LPS（TLR4激动剂）在啮齿动物中产生异常性症，并增加15-lox-1表达； iii）15-lox-1的脊柱或全身抑制作用，但不是Cox，废除了大鼠和小鼠的TLR4介导的异常性疾病，以及IV）大鼠的外周炎症或小鼠中的K/BXN血清转移关节炎可通过几种受体诱导12/15-LMS和异常性疾病。鉴于这些观察结果，本文提出的研究将检验脊柱15-lox的总体假设激活通过3介导K/BXN关节炎期间从急性到慢性疼痛的过渡。通过研究1）脊柱15-LOX-1在急性对K/BXN关节炎疼痛慢性转变2的作用2）脊柱15-LOX-1和3的细胞源（S）15-LOX-1的脊柱受体介导的伤害感作用代谢物使用各种行为（触觉，抓地力，开放场，炎症的临床体征），分子和生化测定。总体而言，预期的结果将解决重大差距理解慢性疼痛和询问的感觉和情感成分的基础机制 15-LOX-1是一种新型的可药物靶标，以阻止多个下游受体激活替代者治疗关节炎状态的治疗策略在炎症解决后持续存在。