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：
9398439
负责人：
Ku-Lung Hsu
金额：
$ 39.14万
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/9398439
关键词：
2-arachidonylglycerol Address Adult Adverse effects Afferent Neurons American Anabolism Anti-Inflammatory Agents Anti-inflammatory Arachidonic Acids Autocrine Communication Behavioral Biological Process Biology Cardiovascular Diseases Cause of Death Cells Chemicals Chronic Chronic Disease Complex Data Development Diabetes Mellitus Dinoprostone Disease Drug Delivery Systems Eicosanoids Encapsulated Endocannabinoids Enzymes G-Protein-Coupled Receptors Gastric Acid Goals Human Immune Industrialization Infection Inflammation Inflammation Mediators Inflammatory Inflammatory Response Injury Intervention Life Lipids Liposomes Malignant Neoplasms Mass Spectrum Analysis Mediating Medical Metabolic Metabolism Methods Modeling Modernization Molecular Mus PTGS2 gene Pain Pathogenesis Pathologic Pathology Pathway interactions Peripheral Phagocytes Pharmaceutical Preparations Phosphotransferases Physiological Physiology Play Production Property Prostaglandin-Endoperoxide Synthase Prostaglandins Proteins Proteomics Publications Publishing Respiration Disorders Signal Pathway Signal Transduction Signaling Molecule Site Societies Stomach TNF gene Testing Therapeutic Tissues Toxic effect addiction autocrine base cell injury cell type chronic pain combat cost cross reactivity cyclooxygenase 1 cytokine eicosanoid metabolism fighting gastrointestinal human disease in vivo inflammatory neuropathic pain inhibitor/antagonist innovation insight lipid metabolism lipoprotein lipase macrophage metabolomics monocyte mouse model novel novel therapeutics pre-clinical response small molecule targeted treatment

项目摘要

Project Summary 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. Here, we plan to test our central hypothesis that DAGLB-inactivation produces anti-inflammatory effects via autocrine lipid signaling pathways in macrophages to reduce local inflammatory responses in vivo. We propose a highly innovative approach that leverages chemical proteomics, mass spectrometry metabolomics, mouse pain models, and novel small molecule probes that selectivity detect and inactivate DAGLB in vivo. The impact of our proposed studies include 1) molecular elucidation of crosstalk between lipid and kinase signaling pathways that explain the anti-inflammatory effects of DAGLB inhibitors, 2) insights into the translational potential of endocannabinoid biosynthetic pathways in human innate immune biology, and 3) creation of new drug delivery strategies for targeting macrophage signaling for treating pathological pain. Our long-term goals are to identify new anti-inflammatory mechanisms and drug delivery strategies for developing targeted anti- inflammatory drugs suitable for treating chronic disease.

项目概要在全球范围内，慢性疾病包括心血管疾病、糖尿病、癌症和慢性呼吸道疾病疾病是工业化社会中最大的死亡原因之一。除了危及生命慢性疼痛目前困扰着数百万美国成年人，每年造成数十亿人死亡医疗费用。虽然复杂的分子因素是这些异质病理的基础，但有一个统一的特征许多慢性疾病的其中一个原因是未解决的炎症。因此，需要新的抗炎靶点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分子这可以引起生理学的深刻变化，包括外周感觉神经元的敏感性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，这对激活促炎至关重要巨噬细胞的反应。最近的初步数据进一步支持 DAGLB 调节的脂质途径是一种安全的途径缺乏炎症和神经病理性疼痛的小鼠模型的干预方法和有效点胃肠道和明显的行为副作用。我们提出的研究建立在我们小组已发表的数据的基础上以及其他人指出巨噬细胞中 DAGLB 调节的通路是一种新的抗炎靶点用于治疗慢性炎症和疼痛。在这里，我们计划测试我们的中心假设，即 DAGLB 失活通过以下方式产生抗炎作用：巨噬细胞中的自分泌脂质信号通路可减少体内局部炎症反应。我们建议一种高度创新的方法，利用化学蛋白质组学、质谱代谢组学、小鼠疼痛模型，以及选择性检测体内 DAGLB 并使 DAGLB 失活的新型小分子探针。影响我们提出的研究包括 1) 脂质和激酶信号传导之间串扰的分子阐明解释 DAGLB 抑制剂抗炎作用的途径，2）对转化的见解内源性大麻素生物合成途径在人类先天免疫生物学中的潜力，以及3）创造新的针对巨噬细胞信号传导治疗病理性疼痛的药物递送策略。我们的长期目标旨在确定新的抗炎机制和药物输送策略，以开发靶向抗炎药物适用于治疗慢性疾病的炎症药物。