Elucidating diacylglycerol lipase beta-mediated effects on neuroinflammatory signaling

阐明二酰甘油脂肪酶β介导的神经炎症信号传导作用

• 批准号: 10156856
• 负责人: Timothy Brandon Ware
• 金额: $ 1.29万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-10 至 2021-05-07
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10156856
• 关键词: Acute; Adenosine Monophosphate; Adult; Afferent Neurons; American; Animals; Anti-Inflammatory Agents; Antiinflammatory Effect; Arachidonic Acids; Attenuated; Behavior; Behavioral; Behavioral Model; Catabolism; Cells; Characteristics; Chronic; Chronic Disease; Chronic inflammatory pain; Collaborations; Complex; Consequentialism; Cytokine Gene; Data; Defense Mechanisms; Diglycerides; Drug Tolerance; Effectiveness; Eicosanoid Production; Eicosanoids; Endocannabinoids; Enzymes; Exhibits; Fatty Acids; Funding; Genes; Genetic; Genetic Transcription; Goals; Homeostasis; Hydrolysis; Immune; Inflammation; Inflammatory; Inflammatory Response; Intervention; Knock-out; Knockout Mice; Learning; Lipids; Lipopolysaccharides; Mass Spectrum Analysis; Mediating; Medical Care Costs; Metabolic; Modeling; Molecular; Mus; Natural Immunity; Nerve; Neuropathy; Nociception; Non-Steroidal Anti-Inflammatory Agents; Opioid; Pain; Pathogenesis; Pathology; Pathway interactions; Peripheral; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacology; Phosphorylation; Phosphotransferases; Physiology; Principal Investigator; Process; Production; Property; Prostaglandins; Protein Kinase; Proteins; Proteomics; Regulation; Research Proposals; Role; Series; Signal Pathway; Signal Transduction; Signaling Molecule; Signaling Protein; Site; Source; Synthetic Prostaglandins; Testing; Therapeutic; Tissues; Training; Translations; Trauma; Work; Writing; addiction; base; behavioral study; cell injury; chronic constriction injury; chronic pain; cytokine; efficacious treatment; immunoregulation; in vivo; inflammatory pain; inhibitor/antagonist; instrument; lipid biosynthesis; lipid metabolism; lipoprotein lipase; macrophage; metabolomics; mouse model; neuroinflammation; nociceptive response; novel; oxidation; pain model; pain relief; pain signal; painful neuropathy; pathogen; protein kinase inhibitor; response; sensory system; side effect; small molecule; small molecule inhibitor; transmission process; treatment strategy

Project Summary/Abstract The overall goal of this proposal is to understand how diacylglycerol lipase beta (DAGLβ) attenuates neuroinflammatory signaling and consequential pain. In response to tissue damage, proinflammatory signals (lipids or cytokines) are released by injured cells and initiate cell-based adaptative and innate immunity mechanisms to protect the host. The activation of these innate immune cells results in a series of immunomodulatory cascades that triggers additional inflammation and the stimulation of nearby nerves, eliciting pain. One of these cascades involves the production of proinflammatory eicosanoid (i.e. prostaglandin) lipids while another cascade centers around the transcription of proinflammatory genes key to cytokine expression. Current pharmacological interventions either work at the site of trauma (i.e. non-steroidal anti-inflammatory drugs, NSAIDs) or in the transmission of resulting pain responses (i.e. opioids). However, none of these therapies provide efficacious long-term treatment as the eventual drug tolerance that builds elicits adverse side effects ranging from chronic disease to addiction. What is desperately needed is a therapy that displays efficacy in not only thwarting inflammatory signaling, but also relieving pain without consequence over long periods of exposure. DAGLβ is an enzyme that directly attenuates eicosanoid production through the hydrolysis of diacylglycerol lipids upstream of the prostaglandin synthetic pathway. Inhibition of DAGLβ has been found to be efficacious in promoting antinociception sourced through either inflammatory (acute) or neuropathic (chronic) pain models. Moreover, long-term DAGLβ inhibitor exposure does not produce characteristic metabolic, behavioral or addictive side effects. A critical gap in our understanding is how DAGLβ attenuates cytokine production as evidence strongly suggests that its role in eicosanoid production does not explain its pain-relieving effects in chronic pain as NSAIDs, which also target eicosanoid production, are often ineffective in these same chronic models. Here we describe a novel connection between DAGLβ activity and kinase-based signaling that is known to regulate proinflammatory cytokine gene transcription. We seek to identify the mechanisms by which DAGLβ regulates neuroinflammatory signaling for the eventual translation of DAGLβ small molecule inhibitors into efficacious therapies for chronic pain alleviation. In this proposal, our first aim is the determine the mechanisms through which DAGLβ activity modulates a kinase-based signaling network, separate from the canonical prostaglandin lipid production pathway. Our second aim is to test the applicability of DAGLβ inhibitors in suppressing nociceptive behaviors displayed by chronically inflamed mice through repeated exposure. Successful completion of this project will broaden our understanding of lipid signaling involved in neuroinflammation, identify novel cross-talk between distinct metabolic signaling pathways, and demonstrate the therapeutic potential of DAGLβ inhibitors in replacing current drug strategies for the treatment of chronic pain.

项目摘要/摘要 该建议的总体目标是了解二酰基甘油脂肪酶β（DAGLβ）如何减弱 神经炎症信号传导和结果性疼痛。响应组织损伤，促炎信号 （脂质或细胞因子）由受伤的细胞释放，并启动基于细胞的适应性和先天免疫力 保护主机的机制。这些先天免疫细胞的激活导致一系列 免疫调节级联反应会触发额外的炎症和刺激附近神经，引起 疼痛。这些级联反应之一涉及产生促炎类花生酸（即前列腺素）脂质 而另一个级联则围绕促炎基因的转录至关重要，这是细胞因子表达的关键。 当前的药理学干预措施要么在创伤部位起作用（即非甾体类抗炎 药物，NSAIDS）或导致疼痛反应的传播（即阿片类药物）。但是，这些疗法都没有 提供有效的长期治疗，作为最终产生的药物耐受性，引起不利的副作用 从慢性疾病到成瘾。迫切需要的是一种疗法，该疗法表现出有效性 只有挫败炎症信号传导，但在长时间暴露期间也可以缓解疼痛而不会导致疼痛。 DAGLβ是一种酶，通过二酰基甘油脂质的水解直接减弱类固醇生产 前列腺素合成途径上游。抑制DAGLβ在 通过炎症（急性）或神经性（慢性）疼痛模型促进抗伤害感受。 此外，长期DAGLβ抑制剂暴露不会产生特征代谢，行为或 加性副作用。我们理解中的一个关键差距是daglβ如何减弱细胞因子的产生为 证据强烈表明，其在类类生产中的作用并不能解释其在疼痛中的影响 慢性疼痛作为NSAID，也靶向eicosanoid的产生，在这些相同的慢性中通常无效 型号。在这里，我们描述了DAGLβ活性与基于激酶的信号传导之间的新型联系 调节促炎性细胞因子基因转录。我们试图确定daglβ的机制 调节DAGLβ小分子抑制剂的事件翻译中的神经炎症信号传导 在此提案中，我们的第一个目的是确定机制 DAGLβ活性通过其中调节基于激酶的信号网络，与规范分开 前列腺素脂质生产途径。我们的第二个目的是测试DAGLβ抑制剂在 通过反复的暴露抑制长期发炎的小鼠表现出的伤害性行为。 成功完成该项目将扩大我们对涉及的脂质信号的理解 神经炎症，确定不同的代谢信号通路之间的新颖串扰，并证明 DAGLβ抑制剂在替代当前药物策略治疗慢性疼痛方面的治疗潜力。