Endocannabinoid Biosynthesis in Inflammation and Pain

炎症和疼痛中的内源性大麻素生物合成

• 批准号: 10400420
• 负责人: Ku-Lung Hsu
• 金额: $ 0.99万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10400420
• 关键词: Adult; Afferent Neurons; American; Anabolism; Anti-Inflammatory Agents; Behavioral; Biology; Bone Marrow; Cardiovascular Diseases; Cause of Death; Chronic; Chronic Disease; Complex; Data; Development; Diabetes Mellitus; Disease; Eicosanoids; Endocannabinoids; Gene Expression; Gene Expression Profiling; Industrialization; Inflammation; Inflammatory; Internships; Intervention; Knock-out; Life; Lipids; Malignant Neoplasms; Medical; Medical Care Costs; Metabolic; Molecular; National Institute of Drug Abuse; Outcome; Pain; Pathogenesis; Pathologic; Pathology; Pathway interactions; Peripheral; Phosphotransferases; Physiology; Play; Proteins; Publishing; Respiration Disorders; Signal Transduction; Signaling Molecule; Site; Societies; Training; Translating; biomarker identification; chronic inflammatory disease; chronic pain; combat; computerized tools; gastrointestinal; inflammatory pain; lipid metabolism; lipoprotein lipase; macrophage; mouse model; non-opioid analgesic; novel; painful neuropathy; programs; response; side effect; summer research; transcriptome sequencing; transcriptomics

Globally, chronic disorders including cardiovascular disease, diabetes, cancer, and chronic respiratory disorders represent one of the largest causes of death in industrialized societies. Besides life- threatening disease, chronic pain currently inflicts millions of American adults and contributes to billions ever year in medical costs. While complex molecular factors underlie these heterogeneous pathologies, a unifying feature of numerous chronic disorders is non-resolved inflammation. Thus, new anti-inflammatory targets are needed to combat the burden of chronic inflammatory disease. Macrophages accumulate at inflammatory sites to produce lipid and protein inflammatory signaling molecules that can cause profound changes in physiology including sensitization of peripheral sensory neurons to promote pathogenesis of chronic pain. We previously discovered that diacylglycerol lipase-beta (DAGLB) regulates an endocannabinoid-eicosanoid lipid-signaling network critical for activation of proinflammatory responses in macrophages. Recent preliminary data further support DAGLB-regulated lipid pathways as a safe and effective point of intervention in mouse models of inflammatory and neuropathic pain that lack gastrointestinal and overt behavioral side effects. Our proposed studies build on published data from our group as well as others that point to DAGLB-regulated pathways in macrophages as a novel anti-inflammatory target for treating chronic inflammation and pain. Sage Cho will be actively involved in analyzing gene expression changes in macrophages where diacylglycerol lipase-beta (DAGLB) has been genetically disrupted in primary bone marrow-derived macrophages (BMDMs). We hypothesize that DAGLB disruption results in alterations in metabolic and signaling programs in BMDMs that result in global reprogramming of macrophage biology. Sage will be actively involved in using computational tools to determine gene expression changes that are statistically significant in DAGLB wild-type (WT) and knockout (KO) BMDMs from recent RNA-seq analyses in our group. The expected outcomes are identification of network wide changes in kinase and other signaling networks that are regulated by DAGLB. The impact of the NIDA Summer Research Internship Program is 1) trainee will receive important training on endocannabinoid lipid signaling and computational approaches for global transcriptomics, and 2) identification of biomarkers of DAGLB activity, which is important for translating this target for development of non-opioid analgesics.

在全球范围内，包括心血管疾病，糖尿病，癌症和慢性病，包括慢性疾病 呼吸系统疾病是工业社会中最大的死亡原因之一。除了生活 - 威胁性疾病，慢性疼痛目前造成数百万美国成年人，并为数十亿 一年的医疗费用。尽管复杂的分子因子是这些异质性病理的基础 许多慢性疾病的统一特征是未解决的炎症。因此，新的抗炎 需要目标来应对慢性炎症疾病的负担。 巨噬细胞在炎症部位积聚以产生脂质和蛋白质炎症信号传导 可能导致生理学深刻变化的分子，包括周围感觉的敏感 神经元促进慢性疼痛的发病机理。我们以前发现二酰基甘油脂肪酶-beta （DAGLB）调节内源性大麻素 - eicosanoid-Sigid-Signaling网络至关重要 巨噬细胞中的促炎反应。最近的初步数据进一步支持DAGLB调节的脂质 途径是炎症和神经性小鼠模型的安全有效的干预点 缺乏胃肠道和明显行为副作用的疼痛。我们提出的研究以出版 来自我们小组的数据以及其他指向巨噬细胞中DAGLB调节的途径的数据 治疗慢性炎症和疼痛的抗炎靶标。 Sage Cho将积极参与分析巨噬细胞中基因表达的变化，其中 二酰基甘油脂肪酶-beta（daglb）已在原发性骨髓衍生的遗传上破坏 巨噬细胞（BMDMS）。我们假设DAGLB破坏会导致代谢和信号的改变 BMDM中导致全球重编程巨噬细胞生物学的程序。圣人将积极参与 在使用计算工具来确定DAGLB中具有统计学意义的基因表达变化时 来自我们小组最近的RNA-Seq分析的野生型（WT）和敲除（KO）BMDM。预期的结果 是识别由DAGLB调节的激酶和其他信号网络中的广泛变化。 NIDA夏季研究实习计划的影响是1）学员将接受重要的培训 全球转录组学的内源性大麻素脂质信号传导和计算方法，2）识别 DAGLB活性的生物标志物，这对于转化这种非阿片类药物的靶标很重要 镇痛药。