自噬负性调控NLRP3炎症小体在干眼眼表微环境自稳态中的作用及机制研究

干眼是最常见的慢性眼表疾病，严重影响生活质量和工作效率。眼表炎症与泪液高渗是其核心发病机制，且两者互为因果，形成恶性循环。但干眼的病情多呈复发缓解的波动性特征；我们前期研究亦发现小鼠干眼模型在干燥环境刺激的后期，其干眼体征竟有所改善，这些均提示干眼的转归存在未知的自稳态机制，干眼自稳态与炎症恶性循环之间的平衡机制亟待研究。本项目前期细胞模型的初步结果揭示自噬负性调控NLRP3炎症小体的表达，在干眼的自稳态过程中可能起着重要作用。在此基础上，项目组拟以维持干眼眼表微环境自稳态为核心：①明确自噬在不同严重程度的干眼患者和疾病模型中的表达特征；②揭示自噬通过保护线粒体完整性、阻止线粒体损伤信号的释放而负性调控NLRP3激活的机制；③在动物模型上探究激活自噬对干眼的预防和治疗的可行性，以期建立维持眼表微环境稳态为基础的干眼防治新策略。

Dry Eye disease (DED), the most common chronic ocular disease, which seriously affects life quality and work efficiency. The core mechanism of DED is tear hyperosmolarity and inflammation on the ocular surface. Evidence indicated that tear hyperosmolarity could initiate a damaging cascade of inflammation at the ocular surface, which could decrease wettability, induce tear film instability and breakup and thereby amplify tear hyperosmolarity. These sequelae lead to a cycle of events termed the Vicious Circle. But DED not only tends to be relapsing but also recovering over time both in symptoms and signs. It is not necessarily progressive over the long term, and most patients report no changes even some level of improvement. Previous studies also showed that in the late stage of dry eye mouse model induced by an Intelligently Controlled Environmental System (ICES), which was established in our lab, the damaged morphology as well as secretion function of ocular surface and lacrimal gland improved. Thus, it is suggested that there are unknown homeostatic mechanisms for the outcome of DED. Our preliminary experiments found that autophagy downregulate NLRP3 inflammasome activity in human corneal epithelial cells (HCESs) induced by hyperosmotic stress. Autophagy may play an important role in maintaining the homeostasis of the ocular surface microenvironment in DED. This study takes maintaining the homeostasis of the ocular surface microenvironment as the core, and the expression characteristics of autophagy and NLRP3 in hyperosmotic stressed HCECs, ICES induced evaporative DED mice model and DED patients will be analyzed. Further to reveal the mechanism of autophagy downregulating NLRP3 inflammasome activity via keeping the integrality of mitochondria membrane and preventing the release of mitochondrial damage signals, which is to explore the practicability of preventing and treating DED on animal models. It is expected useful to investigate the potential for therapeutic targeting of autophagic processes to mitigate DED.