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、癌症和慢性疾病

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.