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.

项目总结/摘要 该提案的总体目标是了解二酰基甘油脂肪酶β（DAGLβ）如何减弱 神经炎性信号传导和随之而来的疼痛。为了应对组织损伤，促炎信号 （脂质或细胞因子）由受损细胞释放并启动基于细胞的适应性和先天性免疫 保护宿主的机制。这些先天免疫细胞的激活导致一系列的免疫反应。 免疫调节级联反应，引发额外的炎症和刺激附近的神经，引发 痛苦这些级联反应之一涉及促炎性类二十烷酸（即前列腺素）脂质的产生 而另一个级联反应围绕着对细胞因子表达起关键作用的促炎基因的转录。 目前的药理学干预要么在创伤部位起作用（即非甾体抗炎药）， 药物，NSAID）或在所产生的疼痛反应的传递中（即阿片类药物）。然而，这些疗法中没有一种 提供有效的长期治疗作为最终的药物耐受性， 从慢性病到成瘾。迫切需要的是一种治疗方法， 不仅能抑制炎症信号，而且能缓解疼痛，长时间接触也不会产生任何后果。 DAGLβ是一种通过水解甘油二酯脂质直接减弱类二十烷酸产生的酶 前列腺素合成途径的上游。已经发现DAGLβ的抑制在以下方面是有效的： 促进来源于炎性（急性）或神经性（慢性）疼痛模型的抗伤害感受。 此外，长期DAGLβ抑制剂暴露不会产生特征性的代谢、行为或代谢异常。 上瘾的副作用我们理解的一个关键差距是DAGLβ如何减弱细胞因子的产生， 有证据有力地表明，它在类花生酸产生中的作用并不能解释它的止痛作用， 慢性疼痛作为NSAID，其也靶向类二十烷酸的产生，在这些相同的慢性疼痛中通常是无效的。 模型在这里，我们描述了DAGLβ活性和基于激酶的信号传导之间的一种新的联系， 调节促炎细胞因子基因转录。我们试图确定DAGLβ 调节神经炎症信号传导，最终将DAGLβ小分子抑制剂翻译成 缓解慢性疼痛的有效疗法。在这项建议中，我们的首要目标是确定机制 DAGLβ活性通过其调节基于激酶的信号网络，与经典的 前列腺素脂质产生途径。我们的第二个目标是测试DAGLβ抑制剂在以下方面的适用性 通过反复暴露，抑制慢性炎症小鼠表现出的伤害性行为。 成功完成这个项目将扩大我们对脂质信号转导的理解， 神经炎症，确定不同的代谢信号通路之间的新的串扰，并证明 DAGLβ抑制剂在替代目前治疗慢性疼痛的药物策略中的治疗潜力。