Endocannabinoid Biosynthesis in Inflammation and Pain

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 呼吸系统疾病是工业化社会中最大的死亡原因之一。除了生活- 威胁疾病的慢性疼痛目前困扰着数百万美国成年人，并为数十亿人做出了贡献 一年的医疗费用。虽然复杂的分子因素是这些异质病理的基础，但 许多慢性疾病的统一特征是未消解的炎症。因此，新的抗炎药 需要制定目标来对抗慢性炎症性疾病的负担。 巨噬细胞聚集在炎症部位，产生脂质和蛋白质炎症信号 可导致生理上的深刻变化的分子，包括外周感觉敏化 神经元促进慢性疼痛的发病机制。我们先前发现二酰甘油脂肪酶-β (DAGLB)调节内源性大麻素-二十烷基类脂类信号网络，对激活 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 通路作为一种安全有效的干预点在小鼠炎症和神经病理性模型中的作用 没有胃肠道和明显的行为副作用的疼痛。我们建议的研究是在已发表的基础上进行的 来自我们小组和其他人的数据表明，巨噬细胞中DAGLB调节的通路是一种新的 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基因表达的变化 二酰甘油脂肪酶-β(DAGLB)在原发骨髓来源的基因中被破坏 巨噬细胞(BMDM)。我们假设DAGLB中断会导致代谢和信号的改变 BMDM中的计划导致巨噬细胞生物学的全球重新编程。Sage将积极参与 在使用计算工具确定在DAGLB中具有统计意义的基因表达变化时 野生型(WT)和敲除(KO)BMDM来自我们组最近的RNA-SEQ分析。预期结果 识别受DAGLB调控的蛋白激酶和其他信号网络中的网络范围的变化。 NIDA暑期研究实习计划的影响是1)学员将接受关于以下方面的重要培训 内源性大麻素类脂信号和用于整体转录的计算方法，以及2)鉴定 DAGLB活性的生物标志物，这对于将这一靶点转化为非阿片类药物的开发是重要的 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.