新型细胞因子FAM3D/Oit1通过募集和活化中性粒细胞促进腹主动脉瘤发生与发展的研究

Abdominal aortic aneurysm (AAA) is a highly lethal vascular disease with the pathological manifestations of vascular inflammation and extracellular matrix degradation. Among various inflammatory cells, neutrophils are firstly recruited into vascular wall during the pathogenesis of AAA. Cytokines are involved in the recruitment and activation of inflammatory cells, thus to explore the critical cytokines working in early stage of inflammation favors the discovery of novel AAA therapeutic targets. FAM3D/Oit1 is a novel cytokine discovered recently, and its expression and function in vascular system are still elusive. We firstly established Oit1-/- mice and found FAM3D/Oit1 deficiency inhibited the elastase-induced AAA in mice and decreased the neutrophil infiltration in vascular wall at early stage of AAA. Moreover, purified FAM3D/Oit1 protein induced neutrophil chemotaxis, ROS production and granule proteins expression in vitro. Therefore, we hypothesized that FAM3D/Oit1 aggravates AAA formation and development via upregulating neutrophil recruitment and activation. As we plan, we will confirm the role of FAM3D/Oit1 in AAA using three kinds of AAA mice models and Oit1-/- mice. Then we will observe the effects of FAM3D/Oit1 on neutrophil chemotaxis, adhesion, degranulation and extracellular trap (NET) formation both in vitro and in vivo, and further will explore the underlying mechanisms of FAM3D/Oit1 in modulation of neutrophil functions. Through this project, we expect to seek for the critical cytokine regulating the early stage of inflammation related to AAA.

腹主动脉瘤是一种以血管炎症和基质降解为主要病理表现的高度致死性血管疾病。中性粒细胞是其发病过程中最早浸润血管壁的炎症细胞。细胞因子参与调控炎症细胞的募集和激活，探索炎症早期的关键致病细胞因子，有助于发现腹主动脉瘤防治的新线索。FAM3D/Oit1是一种新发现的细胞因子，其在血管中的表达及功能尚无报道。我们制备了FAM3D/Oit1敲除小鼠，发现可抑制弹力酶诱导的腹主动脉瘤并且减少早期中性粒细胞的浸润；纯化的FAM3D/Oit1可体外诱导中性粒细胞趋化、ROS释放和颗粒蛋白表达。我们假设：FAM3D/Oit1通过募集和活化中性粒细胞促进腹主动脉瘤的发病。我们将利用不同腹主动脉瘤模型及基因敲除小鼠明确FAM3D/Oit1对腹主动脉瘤的影响；细胞和动物实验检测FAM3D/Oit1对中性粒细胞趋化、粘附、脱颗粒和形成中性粒胞外陷阱NET的调控及其机制；以寻找腹主动脉瘤早期调控炎症的关键细胞因子。

趋化因子介导的免疫细胞募集是腹主动脉瘤致病的重要环节。我们前期合作研究发现一种新型趋化因子FAM3D。本课题主要研究FAM3D对腹主动脉瘤的调控作用及相关机制。我们发现FAM3D缺陷抑制弹力酶诱导的腹主动脉瘤形成，并在疾病早期显著降低中性粒细胞的募集。相关机制为FAM3D作用于中性粒细胞膜上的甲酰肽受体FPR1/2，激活受体下游G蛋白相关和beta-arrestin相关信号，进而活化细胞膜整合素Mac1，促进中性粒细胞的黏附和跨内皮迁。该研究揭示了新型趋化因子FAM3D在腹主动脉瘤中的致病作用，并可作为防治腹主动脉瘤的潜在靶点。此外，我们还发现FAM3D参与介导血管紧张素II诱导的高血压及相关血管重塑，并正在进行机制的探索。项目共发表带标注SCI论文4篇，IF>5的3篇，申请国内专利（含PCT专利）1项。