HOIP酶介导NFAT线性泛素化调控在川崎病中的作用与机制探讨

Kawasaki disease is a systemic immune vasculitis that is characterized by coronary artery lesions. It is closely associated with acquired heart diseases and coronary heart diseases. We previously found that linear ubiquitin enzyme HOIP expressed in KD patients. In vasculitis in KD models, we found that HIOP interacted with NFAT and the ubiquitination signaling of NFAT significantly increased when HOIP was over-expressed. Thus, we try to explore the molecular mechanisms on how HOIP negatively actives NFAT signaling-induced inflammation in KD models. We plan to carry out the following researches: ① Test the levels of HOIP and NFAT in KD patients, and further explore their relationship with NFAT expression and coronary artery endothelial cells injury. ② Test the levels of NFAT, linear ubiquitin signaling of NFAT after overexpression and knockdown of HOIP in KD cell models. ③ Knockdown of HIOP in mice models to explore HIOP effect on linear ubiquitin of NFAT and the expression of inflammatory factors. This study is novel and may provide potential targets for early prevention and treatment of KD.

川崎病（Kawasaki disease, KD）病理特征是全身性免疫性血管炎，主要累及心血管，是成年后冠心病的高危因素。我们前期研究发现线性泛素酶HOIP在KD患儿不同病期均有表达；血管内皮细胞炎性损伤时HOIP与底物NFAT存在相互作用，且过表达HOIP后NFAT线性泛素化水平显著增加。因此我们拟探讨：HOIP调控NFAT信号介导的炎症反应及其在KD发生发展中的作用机制。本项目拟研究：① KD患儿HOIP和NFAT表达水平变化情况，及其与冠状动脉内皮细胞损伤的相关性。②在血管内皮细胞炎性损伤模型上：HOIP过表达/敲降后，检测底物NFAT分子与其结合及线性泛素化水平变化情况。③在鼠KD模型上：研究HOIP对NFAT线性泛素化及炎症因子表达的影响，以系统验证该新机制。本研究具有源头创新性，有望为KD防治提供新线索和干预靶点。

川崎病（Kawasaki disease, KD）主要病理特征是冠状动脉损伤和全身免疫性血管炎，它与儿童后天性心脏病和冠心病密切相关。我们前期研究发现线性泛素酶HOIP在KD患儿不同病期均有表达，证实KD血管炎模型中 HOIP与底物NFAT有相互作用，且过表达HOIP后NFAT线性泛素化水平显著增加。因此我们提出了HOIP靶向NFAT的线性泛素化参与KD血管炎性损伤的机制调控。本研究完成了1、KD患儿不同进程中HOIP和NFAT及其与炎症因子表达水平的相关性；2、细胞中HOIP过表达/表达敲降后，NFAT分子表达水平及其与HOIP结合及线性泛素化水平的变化情况；3、HOIL1敲除小鼠MEF中NFAT1线性泛素化水平显著下调，证实KD病人白细胞中NFAT1线性泛素化水平显著上升，并且与表达增高的HOIL-1L水平呈正相关性。因此，本研究揭示LUBAC一个新的调控底物NFAT1，且KD中NFAT1的线性泛素化修饰在疾病进程中扮演重要角色，顺利完成HOIP酶介导NFAT线性泛素化调控在川崎病中的作用与机制验证。相关文章均发表在国际著名期刊（SCI收录）或北图核心期刊，培养了多名研究生，研究成果有望为今后寻找KD血管炎的致病机制和干预靶点提供新的思路。