Endocannabinoid Biosynthesis in Inflammation and Pain

在全球范围内，包括心血管疾病、糖尿病、癌症和慢性 呼吸系统疾病是工业化社会中最大的死亡原因之一。除了生命- 慢性疼痛是一种威胁性疾病，目前有数百万美国成年人遭受慢性疼痛， 一年的医疗费用。虽然复杂的分子因素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，新的抗炎药 需要有目标来对抗慢性炎性疾病的负担。 巨噬细胞聚集在炎症部位，产生脂质和蛋白质炎症信号 这些分子可以引起生理学上的深刻变化，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-二十烷类脂质信号传导网络，该网络对于激活 巨噬细胞的促炎反应。最近的初步数据进一步支持DAGLB调节的脂质 通路作为炎症和神经病变小鼠模型中安全有效的干预点 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 来自我们小组以及其他人的数据表明，巨噬细胞中DAGL B调节的途径是一种新的 用于治疗慢性炎症和疼痛的抗炎靶点。 Sage Cho将积极参与分析巨噬细胞中的基因表达变化， 二酰基甘油脂肪酶-β（DAGLB）已在原发性骨髓源性 巨噬细胞（BMDM）。我们假设DAGLB破坏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 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， 野生型（WT）和敲除（KO）BMDM，来自我们组中最近的RNA-seq分析。预期成果 是确定激酶和其他信号传导网络中由DAGLB调节的网络范围的变化。 NIDA暑期研究实习计划的影响是：1）学员将接受以下方面的重要培训 内源性大麻素脂质信号传导和全局转录组学的计算方法，以及2）鉴定 DAGLB活性的生物标志物，这对于将该靶点转化为非阿片类药物的发展是重要的。 止痛药

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.