UCP-1和Adropin的选择性缺乏通过PPARs诱导巨噬细胞极化引发ANCA血管炎亚型遗传异质性的机制

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a systemic autoimmune disease with poor prognosis that is prone to respiratory and renal failures. Its target antigens are serine protease 3 (PR3) and myeloperoxidase (MPO).The essential difference exists between the two subtypes and it is urgent need to confirm the immune molecules and cell subgroups. Our previous research found that UCP-1 and Adropin were important determinant factors affecting ANCA-associated vasculitis, whose deficiency induces macrophage polarization to trigger immune vasculitis. However, the specific mechanism is still unclear. This study will focus on exploring the correlation between the selective deficiency of UCP-1 and Adropin and the different subtypes of ANCA vasculitis. Firstly,we must confirm the dose effect relationship between serum PR3-ANCA or MPO-ANCA and UCP-1 or Adropin, and then to discuss the pathway and mechanism of macrophage polarization induced by PPARs,under the condition of UCP-1 and Adropin deficiency,based on immune cell subsets. Finally, we intend to construct UCP-1KO mice and AdrKO mice to investigate the procedural differences of macrophage polarization with different gene knockouts. We are going to explore the novel mechanism of AAV from the clinical experience, in vitro and in vivo, which is expected to uncovered a novel therapeutic targets.

抗中性粒细胞胞浆抗体（ANCA）相关性血管炎（AAV）是一种系统性自身免疫性疾病，容易累及肺、肾等，预后差，存在PR3血管炎和MPO血管炎两个表型差别较大的亚型，临床迫切需要尽早明确其免疫分子和细胞亚群。我们前期发现UCP-1和Adropin缺乏可诱导巨噬细胞极化、进而引发免疫性血管炎，是ANCA相关性血管炎类型的重要决定因子，但其具体机制不明。本课题将针对UCP-1和Adropin的选择性缺乏与ANCA血管炎遗传异质性之间的相关性开展如下研究：首先确认血清PR3-ANCA和MPO-ANCA阳性患者与UCP-1和Adropin的量效关系；进一步基于免疫细胞亚群，研究UCP-1和Adropin缺乏通过PPARs诱导巨噬细胞极化的通路及机制；同时，构建UCP-1KO和AdrKO小鼠，探讨在不同基因敲除背景下，巨噬细胞极化的程序性差异。课题从多维度探讨AAV致病的新机制，有望发现新的治疗靶标。

抗中性粒细胞胞浆抗体（ANCA）相关性血管炎（AAV）是一种系统性自身免疫性疾病，容易累及肺、肾等，预后差，存在PR3血管炎和MPO血管炎两个表型差别较大的亚型，临床迫切需要尽早明确其免疫分子和细胞亚群。我们前期发现UCP-1和Adropin缺乏可诱导巨噬细胞极化、进而引发免疫性血管炎。.在国家自然科学基金No.81871293资助下，课题组针对Adropin和UCP-1等能量因子影响免疫功能的机制进行深入研究，共累计发表基金标注论文或综述SCI收录8篇，其中JCR一区《Carbon》1篇；JCR二区5篇《Oxid Med Cell Longev》3篇、《Inflammation》1篇和《Drug Delivery》1篇；JCR四区2篇分别是《Gastroenterology Research and Practice》和《Genes & Immunity》。而且多篇论文已经被正面引用，单篇最高被引38次。主要成果体现在以下几点：.1.炎症性肠病患者血清PAB和ANCA阳性率与年龄和性别关联.研究发现女性IBD患者ANCA-IgG和IgA的阳性率高于男性患者，而PAB-IgG的阳性率刚好相反。此外，ANCA IgG和IgA阳性患者的中位年龄高于抗体阴性患者，而PAB IgG和IgA阳性患者的中位年龄显著低于PAB阴性患者。.2.阐述了能量调节因子Adropin免疫学效应.adropin在多种炎症性疾病中的表达水平降低，与炎症相关细胞因子表达水平呈负相关，具有潜在的抗炎作用。.3.CALCA和CALCB高甲基化可能影响妊娠血管适应是极早产和血管炎的重要原因.4.季铵碳量子点作为革兰氏阳性菌抑制剂治疗小鼠MRS感染性肺炎的机制研究.5.IgG4-RD患者中存在抗髓鞘索结合糖蛋白（MAG）抗体。.6.利用纳米载药技术靶向递送CGRP抑制炎症.该工作的展开，为多肽药物的临床转化中具有一定的研究价值。.7.共同性外斜视患者泪液中炎症因子IL-17A和TNF-α的表达增高，可能是促进共同性外斜视患者干眼症发生的潜在因素。.8.免疫伪装—Neu5Gc引发自身免疫与移植排斥机制.9.AdrKO的病理基础是内皮细胞粘附并激活中性粒细胞以释放MPO，然而，UCP-1-KO诱导PR3释放，组织因子在血管壁上积聚和表达。