Targeting GPR109A for the treatment of pain in systemic lupus erythematosus

靶向 GPR109A 治疗系统性红斑狼疮疼痛

• 批准号: 10553567
• 负责人: Han-Rong Weng
• 金额: $ 43.52万
• 依托单位: CALIFORNIA NORTHSTATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-10-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10553567
• 关键词: Adipocytes; Agonist; Analgesics; Animals; Anti-Inflammatory Agents; Antiinflammatory Effect; Attenuated; Behavior assessment; Calcium Channel; Calcium Channel Blockers; Cell Culture Techniques; Cells; Chemicals; Clinic; Clinical; Clinical Treatment; Clinical Trials; Consumption; Coupled; Data; Development; Disease; Drug usage; Dyslipidemias; Embryo; Etiology; G-Protein-Coupled Receptors; Generations; Genetic; Glutamates; Goals; Human; Immune; Immune response; Impairment; Indomethacin; Inflammation Mediators; Interleukin-1 beta; Kidney; Lead; Light; Lupus; Macrophage Activation; Macrophage Colony-Stimulating Factor; Macrophage Colony-Stimulating Factor Receptor; Medical; Microglia; Molecular; Molecular Biology; Mus; N-Type Calcium Channels; Nicotinic Acids; Non-Steroidal Anti-Inflammatory Agents; Nonesterified Fatty Acids; Pain; Pain management; Pathologic; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Play; Process; Production; Productivity; Publications; Quality of life; Reporting; Role; Safety; Signal Pathway; Specificity; Spinal; Spinal Cord; Spine pain; Synaptic Transmission; Systemic Lupus Erythematosus; Techniques; Testing; Time; Tissues; Treatment Efficacy; base; cell type; chronic pain; chronic painful condition; cost effective; cytokine; dorsal horn; human model; lupus prone mice; mortality; mouse model; multidisciplinary; nervous system disorder; neuroinflammation; novel; novel therapeutics; pain signal; patch clamp; receptor; spontaneous pain; therapeutic development

Chronic pain in systemic lupus erythematosus (SLE) significantly impairs the quality of life and productivity of patients due to the lack of potent and safe painkillers. There is a highly unmet need for the development of novel analgesics. Surprisingly, no animal studies had been reported about the mechanisms underlying chronic pain in SLE until our recent study. We found that activation of microglial macrophage colony- stimulating factor-1 (M-CSF1) receptors and over-production of IL-1β in the spinal dorsal horn play a crucial role in the enhancement of spinal excitatory glutamatergic synaptic transmission and generation of chronic pain in a lupus mouse model, MRL lupus prone (MRL/lpr) mice. Our study demonstrated that controlling the spinal neuroinflammation is an effective approach for the treatment of pain in lupus. GPR109A was newly identified in different immune cell types and its activation produces anti-inflammatory effects. Whether and how spinal GPR109A regulates spinal neuroinflammation and the genesis of pathological pain (including chronic pain in SLE) is unknown. Our overarching hypothesis is that activation of the anti-inflammatory receptor GPR109A in spinal microglia attenuates SLE-induced chronic pain and microglial production of pro- inflammatory mediators, in part, through suppressing microglial N-type calcium channel activity. This hypothesis will be tested in 3 specific aims using a well-established mouse model of human SLE, MRL/lpr lupus-prone mice: 1. To test the hypothesis that chronic pain in MRL/lpr mice is reduced by activation of spinal GPR109A; 2. Test the hypothesis that calcium channels are open (activated) in spinal microglia of MRL/lpr mice with chronic pain, and activation of GPR109A suppresses microglial N-type Ca2+ channel activity in MRL/lpr mice with chronic pain; 3. To test the hypothesis that microglial activation and production of pro-inflammatory mediators are regulated by N-type Ca2+ channels and GPR109A. We will apply multidisciplinary cutting edge techniques (including molecular biology, cell culture, genetics, pharmacology, ex-vivo patch-clamp recording, and behavioral assessments) to reach these aims. This study is the first to uncover analgesic effects of the GPR109A activator and its underlying mechanisms. As GPR109A agonists have been in clinical trials for the treatment of dyslipidemia, completion of this project will result in a novel therapeutic use of these drugs, and a faster, cheaper, and less risky development of analgesics, which has high potential for “fast-track” clinical approval for their use in patients. Given that spinal neuroinflammation is a common feature shared by many chronic pain conditions, the results collected in the study may also provide a base for the use of GRP109A agonists for the treatment of other chronic pain conditions.

系统性红斑狼疮 (SLE) 的慢性疼痛显着损害患者的生活质量和生产力 由于缺乏有效且安全的止痛药，患者受到困扰。发展需求远未得到满足 新型镇痛药。令人惊讶的是，目前还没有关于其潜在机制的动物研究报道。 直到我们最近的研究为止，系统性红斑狼疮的慢性疼痛。我们发现小胶质细胞巨噬细胞集落的激活 刺激因子 1 (M-CSF1) 受体和脊髓背角 IL-1β 的过量产生起着至关重要的作用 在增强脊髓兴奋性谷氨酸突触传递和慢性神经元生成中的作用 狼疮小鼠模型、MRL 狼疮倾向 (MRL/lpr) 小鼠的疼痛。我们的研究表明，控制 脊髓神经炎症是治疗狼疮疼痛的有效方法。 GPR109A是新 在不同的免疫细胞类型中被识别，其激活产生抗炎作用。是否和 脊髓 GPR109A 如何调节脊髓神经炎症和病理性疼痛（包括 SLE 的慢性疼痛）尚不清楚。我们的首要假设是抗炎物质的激活 脊髓小胶质细胞中的受体 GPR109A 可减轻 SLE 诱导的慢性疼痛和小胶质细胞产生的亲 炎症介质的部分作用是通过抑制小胶质细胞 N 型钙通道活性来实现的。这 将使用成熟的人类 SLE、MRL/lpr 小鼠模型在 3 个特定目标中测试假设 易患狼疮的小鼠： 1. 检验以下假设：MRL/lpr 小鼠的慢性疼痛可通过激活 脊髓GPR109A； 2. 检验脊髓小胶质细胞中钙通道开放（激活）的假设 患有慢性疼痛的 MRL/lpr 小鼠，GPR109A 的激活抑制小胶质细胞 N 型 Ca2+ 通道 患有慢性疼痛的 MRL/lpr 小鼠的活性； 3. 检验小胶质细胞激活和产生的假设 促炎介质受 N 型 Ca2+ 通道和 GPR109A 调节。我们将申请 多学科尖端技术（包括分子生物学、细胞培养、遗传学、药理学、 离体膜片钳记录和行为评估）以实现这些目标。这项研究首次 揭示 GPR109A 激活剂的镇痛作用及其潜在机制。作为 GPR109A 激动剂 已经处于治疗血脂异常的临床试验中，该项目的完成将产生一种新的 这些药物的治疗用途，以及更快、更便宜、风险更小的镇痛药的开发， 其在患者中使用的“快速”临床批准的潜力很大。鉴于脊髓神经炎症 这是许多慢性疼痛疾病的共同特征，该研究收集的结果也可能 为使用 GRP109A 激动剂治疗其他慢性疼痛奠定了基础。

项目成果

Phytohormone abscisic acid ameliorates neuropathic pain via regulating LANCL2 protein abundance and glial activation at the spinal cord.

• DOI: 10.1177/17448069221107781
• 发表时间: 2022-04
• 期刊: MOLECULAR PAIN
• 影响因子: 3.3
• 作者: Maixner, Dylan W.;Christy, David;Kong, Lingwei;Viatchenko-Karpinski, Viacheslav;Horner, Kristen A.;Hooks, Shelley B.;Weng, Han-Rong
• 通讯作者: Weng, Han-Rong

Activation of microglial GPR109A alleviates thermal hyperalgesia in female lupus mice by suppressing IL-18 and glutamatergic synaptic activity.

• DOI: 10.1002/glia.24130
• 发表时间: 2022-04
• 期刊: GLIA
• 影响因子: 6.2
• 作者: Viatchenko-Karpinski, Viacheslav;Kong, Lingwei;Weng, Han-Rong
• 通讯作者: Weng, Han-Rong

Interleukin-1beta released by microglia initiates the enhanced glutamatergic activity in the spinal dorsal horn during paclitaxel-associated acute pain syndrome.

在紫杉醇相关的急性疼痛综合征期间，小胶质细胞释放的白介素-1β启动脊髓背角谷氨酸能活性的增强。

• DOI: 10.1002/glia.23557
• 发表时间: 2019
• 期刊: GLIA
• 影响因子: 6.2
• 作者: Xisheng Yan;Fen Li;Dylan W Maixner;Ruchi Yadav;Mei Gao;Mourad Wagdy Ali;Shelley B Hooks;Han-Rong Weng
• 通讯作者: Han-Rong Weng

Emerging roles of GPR109A in regulation of neuroinflammation in neurological diseases and pain.

• DOI: 10.4103/1673-5374.354514
• 发表时间: 2023-04
• 期刊: Neural regeneration research
• 影响因子: 6.1
• 作者: Taing K;Chen L;Weng HR
• 通讯作者: Weng HR

Deficient AMPK activity contributes to hyperexcitability in peripheral nociceptive sensory neurons and thermal hyperalgesia in lupus mice.

• DOI: 10.1371/journal.pone.0288356
• 发表时间: 2023
• 期刊: PloS one
• 影响因子: 3.7