中性粒细胞线粒体在川崎病免疫性血管炎症中的作用及新机制

Kawasaki disease is the most common systemic immune vasculitis in children and is considered the high risk factor for adult coronary heart disease. Our previous study found that neutrophils (NEU) increased during the acute stage and was associated with the prognosis of the disease. It was reported that increased NEU was related to the inhibited mitochondrial-dependent apoptotic pathway. We found that nucleus factor of activation of T cell (NFAT) played a role in the pathogenesis of KD by interacting with NEU predicted by systems biology methods. Bioinformatics analysis indicated its target gene was VDAC3 in mitochondria and VDAC3 was proved down-regulated in KD. Therefore, we hypothesize that NEU NFAT2 targets to VDAC3 to regulate NEU apoptosis and finally leads to immune vasculitis. Here, we plan to carry out the following researches: 1) Clarify the role of NFAT2 in NEU apoptosis. 2) Clarify the role of VDAC3 in NEU apoptosis. 3) Clarify the role of NEU NFAT2 on VDAC3 expression. 4) Clarify the relationship among the expression levels of NFAT2 and VDAC3, the NEU apoptosis and coronary lesion in children with KD. This mechanism hasn’t been studied yet, and may provide potential targets for early prevention and treatment of KD.

川崎病(KD)是儿童最常见的全身性免疫性血管炎，被公认是成年后冠心病的高危因素。我们前期研究证实：中性粒细胞(NEU)在KD急性期增高且与KD预后相关，文献报道NEU增高与其线粒体途径细胞凋亡减慢有关，系统生物学方法预测：核转录因子(NFAT)与NEU的交互作用与KD血管损伤有关。生物信息学预测NFAT2的靶基因是线粒体的VDAC3，且预实验证实NEU VDAC3在KD中降低，因此我们设想：中性粒细胞NFAT2靶向线粒体VDAC3调控中性粒细胞凋亡致KD免疫性血管炎症的新机制。本研究拟进行①NFAT2在NEU凋亡中的作用。②VDAC3在NEU凋亡中的作用。③NEU NFAT2对VDAC3表达的调控作用。④KD患儿外周血NEU NFAT2、VDAC3表达水平与NEU凋亡、冠脉损害的相关性。研究具有创新性，可为KD防治提供新线索和干预靶点。

川崎病(KD)是儿童最常见的全身性免疫性血管炎，被公认是成年后冠心病的高危因素。本项目对KD患儿外周血中性粒细胞中差异性表达的且与线粒体相关的基因VDAC3及NFAT2进行研究，以便发现其线粒体层次的致病作用及可能的新机制，为川崎病的早期诊断及干预治疗提供新的理论依据和潜在的干预靶标。我们研究了（1）川崎病患儿外周血中性粒细胞中NFAT2及VDAC3 DNA水平，发现KD患儿NFAT2及VDAC3 DNA水平降低，治疗后恢复正常，在冠脉扩张与无扩张的患者中无差异。NFAT2和VDAC3水平呈正相关。（2）体内实验：重复构建KD小鼠动物模型，选择8mg CAWS为我们以后行小鼠KD血管损伤模型的适宜浓度，并揭示miR-223-3p通过调控IL-6/IL6ST-STAT3信号通路减轻KD血管内皮损伤。