Endocannabinoid Biosynthesis in Inflammation and Pain

项目摘要 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在内的慢性疾病 疾病是工业化社会中最大的死亡原因之一。除了有生命危险 疾病，慢性疼痛目前造成数百万美国成年人，并有助于数十亿每年在 医疗费用。虽然复杂的分子因素是这些异质性病理的基础，但一个统一的特征是， 许多慢性疾病中的一个是未解决的炎症。因此，需要新的抗炎靶点 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分子 这可能会导致生理学上的深刻变化，包括外周感觉神经元的敏感化， 促进慢性疼痛的发病机制。我们以前发现，二酰基甘油脂肪酶-β（DAGLB） 调节内源性大麻素-二十烷酸类脂质信号传导网络， 巨噬细胞的反应。最近的初步数据进一步支持DAGLB调节的脂质途径是安全的 和有效的干预点，在小鼠模型的炎症和神经性疼痛，缺乏 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公布的数据基础上 以及其他指出巨噬细胞中DAGL B调节途径作为新的抗炎靶点的研究 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，DAGLB失活产生抗炎作用，通过 巨噬细胞中的自分泌脂质信号传导途径以减少体内局部炎症反应。我们提出 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，以及在体内选择性检测和标记DAGLB的新型小分子探针。的影响 我们提出的研究包括：1）脂质和激酶信号之间串扰的分子阐明 解释DAGLB抑制剂抗炎作用的途径，2）对翻译的见解 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 用于靶向巨噬细胞信号传导以治疗病理性疼痛的药物递送策略。我们的长期目标 是为了确定新的抗炎机制和药物输送策略，以开发有针对性的抗炎药物。 适用于治疗慢性疾病的抗炎药。

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.