基于肺泡毛细血管内皮屏障功能研究S1P1/S1P3在特发性肺纤维化中的调控机制及新型药靶鉴定

Idiopathic pulmonary fibrosis (IPF) is a respiratory disorder with high mortality, not well-known etiology and no effective therapeutic strategy. Recent studies have shown that the maintenance of the alveolar capillary endothelial barrier and its function plays a vital role in the pathogenesis of IPF. SYL927 is a novel selective sphingosine-1-phosphate receptor 1 (S1P1) regulator designed and selected by our team, which can reverse epithelial mesenchymal transition and promote capillary endothelial junction to protect alveolar capillary endothelial barrier and subsequently improve pulmonary fibrosis in bleomycin induced lung fibrosis mouse model. Interestingly, previous studies demonstrated that activation of S1P3 and S1P1 at the same time showed no improvement on IPF, suggesting that SIP1 may be a potential drug target for IPF. According to this phenomenon, our team plan to use S1P1-/- and S1P3-/- transgenic animal as well as gene silencing technology to identify the biological function and regulation mechanism of S1P1 and S1P3 in IPF based on alveolar capillary endothelial barrier. Therefore we can illustrate whether S1P1 can be a drug target of IPF and the role of S1P3. In addition, it will help to find novel medicine for IPF and new strategy in the IPF therapy.

特发性肺纤维化（IPF）是一种高死亡率的呼吸系统疾病，确切发病机制不明且无特效治疗药物。近年研究表明，肺泡毛细血管内皮屏障及其功能维持在IPF的发病过程中具有重要作用。SYL927是本课题组发现的全新结构鞘氨醇-1-磷酸-1型受体（S1P1）调节剂，能够逆转小鼠特发性肺纤维化组织的上皮间质转化，促进毛细血管内皮紧密连接，保护屏障功能，并显著改善肺纤维化，而以往研究表明在激活S1P1的同时激活S1P3则对IPF无改善作用，提示SIP1可能是IPF潜在的药物靶点。本项目拟依托SYL927作用于S1P1的分子事件，利用S1P1-/-和S1P3-/-转基因动物、基因沉默等技术，基于肺泡毛细血管内皮屏障功能，深入研究S1P1及S1P3在IPF中的生物学功能及调控机制，以明确S1P1作为IPF治疗的新靶标以及S1P3在其中发挥的作用，并发现抗IPF的全新药物，为IPF的临床治疗提供新的契机和策略。

特发性肺纤维化是一种发病机制尚未明确的严重呼吸系统疾病，且无特效治疗药物，发现针对肺纤维化机制的新靶点和新药具有重要科学意义和实际应用价值。近年来研究表明，肺泡屏障的完整性破坏及功能损伤与肺纤维化的发生发展密切相关。申请人前期研究发现，选择性S1P1激动剂SYL927能够有效保护肺泡屏障，逆转小鼠纤维化，而S1P1/S1P3激动剂FTY720对肺纤维化无效。.为了验证S1P1是否可作为IPF潜在靶点，本研究建立了血管内皮S1P1条件性敲除转基因动物和肺泡上皮S1P3条件性敲除转基因动物。通过生物信息学，多组学，及分子药理学等研究发现 1）S1P1敲除可破坏内皮紧密连接，加重肺纤维化表型，选择性激动S1P1能够保护内皮屏障稳态并逆转凝血酶诱导的屏障损伤。2）S1P3敲除或功能抑制，可保护上皮屏障完整性，逆转上皮间质转化。3）SYL927能够通过选择性激动S1P1发挥屏障保护治疗肺纤维化，而FTY720不但激动S1P3，亦能够导致S1P1内陷后出现泛素化降解，从而降低S1P1表达，破坏屏障稳态功能。相关研究发表于APSB杂志，IF=14.9，SYL927治疗肺纤维化的新应用也申请了相关专利。.本研究不但揭示了选择性激动S1P1可通过全新的肺泡屏障保护机制治疗肺纤维化，确证了S1P1可作为肺纤维化的潜在新靶点，也发现了肺纤维化治疗的潜在新药。为肺纤维化的发病机制拓展及治疗药物研发奠定了很好的实验基础和科学依据。