A型清道夫受体介导的胞葬作用对炎症急性呼吸窘迫综合征的改善机制及其药物调控

急性呼吸窘迫综合征（ARDS）是肺炎等疾病最严重的并发症，伴有肺部中性粒细胞持续升高和透明膜形成。中性粒细胞凋亡和胞外捕捉网（NETs）形成是肺部微血管循环障碍和炎性渗出的主要成因，而巨噬细胞A型清道夫受体(SARCA)介导的胞葬作用是清除NETs和改善ARDS的关键。然而，SARCA转位上膜的分子机制不清，调控手段匮乏。我们前期研究发现，（1）能量调节关键分子AMPK能够促进SCARA转位上膜并吞噬PAMPs/DAMPs。（2）AMPK能结合内质网蛋白GPR37，而GPR37特异性表达在巨噬细胞中并和吞噬功能相关。（3）化合物甲异靛选择性结合GPR37蛋白，抑制炎症。因此，本研究希望：1）阐明AMPK-GPR37-SCARA的层级调控机制，为调控胞葬作用提供新的干预靶标；2）阐明甲异靛与GPR37的分子间相互作用模式，以期为临床治疗炎症性ARDS提供候选药物。

Acute respiratory distress syndrome (ARDS) is the most serious complication of viral pneumonia and other diseases, accompanied by the continuous rise of neutrophils and formation of hyaline membrane in lungs. Neutrophil extracellular traps (NETs) may be the main cause of inflammatory fibromyxoid exudate which resulted in ARDS. Type A scavenger receptor (SARCA), which not only has the function of efferocytosis but also induces macrophages to M2 type after cells being activated, may be the key molecule to attenuate respiratory distress. However, the molecular mechanism of the SARCA translocation from the endoplasmic reticulum to the cell membrane is unclear; and the regulatory strategy of this process are scarce. In previous researches we have found that (1) AMPK, the key molecule in energy regulation, can promote the translocation and phagocytosis of PAMPs/DAMPs of SCARA; (2) In this process, AMPK binds endoplasmic reticulum GPR37, which is a protein specifically expressed in macrophages and is related to cell phagocytosis; (3) The small compound meisoindigo can selectively bind GPR37 and enhance efferocytosis to inhibit inflammation. In this study we hope to solve two key problems: (1) To clarify the mechanism of AMPK-GPR37 in macrophages to regulate the translocation of SCARA onto membrane in order to provide new targets for the therapy of ARDS; 2) To clarify the molecular mechanism of interaction between meisoindigo and GPR37, and to develop candidate drugs for clinical treatment of viral pneumonia.