中链脂肪酸受体作为抗炎症性肠病药物作用新靶点的研究

Inflammatory bowel diseases (IBD) are relapsing-remitting conditions characterized by uncontrolled intestinal inflammation and tissue destruction. IBD include Crohn’s disease (CD) and ulcerative colitis (UC). Recent studies indicate the increasing incidence and prevalence of both CD and UC worldwide, highlighting the urgent need for effective therapeutic options. G protein-coupled receptors form one of the largest drug target family. Medium-chain free fatty acid receptor GPR84 is a GPCR expressed mainly in the immune-related tissues such as spleen, bone marrow and peripheral blood leukocytes, indicating possible roles in inflammatory diseases. Our preliminary studies demonstrated that GPR84 was upregulated in peripheral leukocytes and in colon tissues in DSS-induced mice model of IBD. GPR84 knockout significantly reduced the severity of IBD in mice, indicating that GPR84 is a potential drug target for the treatment of IBD. We also identified a novel GPR84 antagonist CLH536 by high-throughput screening. Oral administration of CLH536 also significantly reduced the severity of IBD in mice. These preliminary results indicate GPR84 play important roles in IBD and may represent a novel drug target. In this proposal, we plan to study in detail the mechanisms of GPR84 in the initiation and development of IBD; we would also collaborate with physicians to collect samples from IBD (including CD and UC) patients to see possible expression differences or polymorphism in GPR84; we would also structurally modify CLH536 to obtain GPR84 antagonists with better in vitro and in vivo activities. Hopefully, with these studies, we would be able to understand the role of GPR84 in IBD and generate GPR84 antagonists worthy of further investigation in preclinical studies.

炎症性肠病（IBD）是肠道免疫系统异常导致的慢性炎性疾病，导致腹痛、腹泻、便血和体重减轻，严重危害健康。IBD发病机制复杂，迄今无药物可治愈，因此新靶点的发现及新药物的研发具有广阔前景。中链脂肪酸受体GPR84属于G蛋白偶联受体家族，主要表达在免疫细胞中，可能参与炎症调控。我们前期研究发现小鼠结肠及外周血白细胞中的GPR84随肠炎进展而上调；在DSS诱导的IBD模型中，GPR84敲除小鼠的症状比野生型小鼠有所改善，提示该受体可能在肠炎中发挥重要作用。我们通过筛选发现一个全新结构的GPR84拮抗剂CLH536，口服可明显缓解小鼠的肠炎症状。以上结果说明GPR84可能是IBD治疗的新靶点。本项目将利用GPR84敲除小鼠及各类肠炎病人的组织深入研究GPR84参与IBD发病的机制，并继续研究GPR84拮抗剂在肠炎动物模型中的药效，希望阐明GPR84在肠炎中的功能并发现靶向该受体的新药候选化合物。

炎症性肠病严重危害人民生命健康。我们发现活动期肠炎病人尤其是溃疡性结肠炎病人的肠黏膜组织中中链脂肪酸受体GPR84表达量显著高于健康人。敲除或抑制GPR84可显著缓解小鼠肠炎相关症状。GPR84主要是通过调节NLRP3通路来调节促炎型巨噬细胞的功能，从而参与炎症性肠病发生发展。我们通过高通量筛选获得全新骨架的GPR84拮抗剂，通过构效关系研究获得数个系列最佳活性达到nM级别的拮抗剂。目前有1个化合物已完成系统临床前研究，在2022/10/20递交PreIND申请（2022005057），预计明年可以开展1期临床研究，用于治疗肠炎。我们还系统开展GPCR结构和功能研究，解析多个受体的配体识别及激活机制；初步研究TGR5，GPR3等受体在肠炎中的作用；发现孤儿受体对髓鞘的再生作用；发现肝脏再生中的关键因子等。已发表SCI论文18篇（18篇IF>5，6篇IF>10，2篇IF>40）。申请专利9项，获授权专利17项。培养博士研究生20名，硕士研究生12名。培养的博士生中已有四名晋升为副研究员，两名获得“中科院青促会”人才项目。申请人谢欣获万人计划科技创新领军人才（2018），中国青年科技奖（2019）等荣誉，也获得基金委群体项目支持。