Endocannabinoid Biosynthesis in Inflammation and Pain

炎症和疼痛中的内源性大麻素生物合成

基本信息

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
项目类别：
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

项目摘要

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，慢性疾病包括心血管疾病、糖尿病、癌症和慢性病呼吸系统疾病是工业化社会中最大的死亡原因之一。除了生活—— 慢性疼痛是一种威胁性疾病，目前困扰着数百万美国成年人，并造成数十亿人死亡年的医疗费用。虽然复杂的分子因素是这些异质病理的基础，许多慢性疾病的共同特征是未解决的炎症。因此，新的抗炎药需要制定目标来对抗慢性炎症疾病的负担。巨噬细胞在炎症部位积聚，产生脂质和蛋白质炎症信号可以引起生理学深刻变化的分子，包括外周感觉的敏化神经元促进慢性疼痛的发病机制。我们之前发现二酰基甘油脂肪酶-β (DAGLB) 调节内源性大麻素-类二十烷酸脂质信号网络，该网络对于激活巨噬细胞的促炎症反应。最近的初步数据进一步支持 DAGLB 调节脂质途径作为炎症和神经病变小鼠模型安全有效的干预点没有胃肠道和明显的行为副作用的疼痛。我们提出的研究建立在已发表的我们小组以及其他小组的数据表明巨噬细胞中 DAGLB 调节的途径是一种新的途径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的基因表达变化，其中二酰基甘油脂肪酶-β (DAGLB) 在原代骨髓来源中已被基因破坏巨噬细胞（BMDM）。我们假设 DAGLB 破坏会导致代谢和信号传导的改变 BMDM 中的程序导致巨噬细胞生物学的全局重编程。 Sage将积极参与使用计算工具确定 DAGLB 中具有统计显着性的基因表达变化来自我们小组最近的 RNA-seq 分析的野生型 (WT) 和敲除 (KO) BMDM。预期成果是鉴定由 DAGLB 调节的激酶和其他信号网络的网络范围变化。 NIDA 暑期研究实习计划的影响是 1) 受训者将接受以下方面的重要培训用于全局转录组学的内源性大麻素脂质信号传导和计算方法，以及 2) 鉴定 DAGLB 活性的生物标志物，这对于将该目标转化为非阿片类药物的开发非常重要镇痛药。