肺纤维化Caveolin1 泛素化降解机制和氟非尼酮治疗靶点的研究

项目名称： 肺纤维化Caveolin1 泛素化降解机制和氟非尼酮治疗靶点的研究

项目编号： No.81470255

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 孟婕

作者单位： 中南大学

项目金额： 75万元

中文摘要： 肺纤维化严重危害人类健康，其发病机制复杂，治疗困难。研究认为，小窝蛋白1(CAV1)表达下降和其调控的多条信号通路异常，在肺纤维化发病中起重要作用；但CAV1表达下调的机制有待阐明，而上调CAV1是治疗肺纤维化的理想策略。氟菲尼酮(AKF-PD)是本课题组发明的新型抗纤维化药物，已经申请进入国家1类新药Ⅰ期临床试验。前期研究发现，AKF-PD能够提高CAV1、治疗肺纤维化；进一步发现AKF-PD抑制CAV1的降解，但不促进CAV1合成。据此我们设想：CAV1泛素化降解异常是肺纤维化的重要机制，AKF-PD通过抑制CAV1泛素化降解而起抗肺纤维化作用。本项目将利用CAV1-/-小鼠、泛素连接酶Cbl-b-/-小鼠和细胞模型开展研究，以探明CAV1泛素化加速是肺纤维化CAV1表达减少的主要原因，泛素连接酶Cbl-b在CAV1降解中起重要作用，CAV1泛素化是AKF-PD治疗肺纤维化的作用靶点。

中文关键词： 肺纤维化；小窝蛋白1；泛素化；氟非尼酮；治疗靶点

英文摘要： Pulmonary fibrosis is a disease which does great harm to human health, with complicated pathological mechanism and poor response to present treatments. Caveolin 1(CAV1) is suggested to play a critical role in the pathogenesis of pulmonary fibrosis according to researches, by its own downregulation and regulation of various signal pathways. But the reason of its downregualtion in fibrosis is still unknown, and upregulation of CAV1 is thought to be an ideal therapeutic strategy. Fluorofenidone (AKF-PD) is novel anti-fibrotic medicine developed by our research group, which has been applied for the clinicalⅠtrials. Previous studies showed that it could increase the expression of CAV1 and had a therapeutic effect to pulmonary fibrosis. Further study found that AKF-PD could also inhibit the degradation of CAV1 while do not affect its synthesis. Based on these findings, we assume that abnormality of CAV1 ubiquitination may be an important mechanism of pulmonary fibrosis, and AKF-PD can protect from pulmonary fibrosis by inhibiting it. We intend to use CAV1-/- and ubiquitin ligase E3 Cbl-b-/- mice and cells as subjects, to investigate whether accelerated ubiquitination is the main reason of downregulation of CAV1 in pulmonary fibrosis, and whether ubiquitin ligase E3 Cbl-b plays an important role in this process, and be an effective target of AKF-PD in the treatment of pulmonary fibrosis.

英文关键词： Pulmonary Fibrosis;Caveolin1;Ubiquitination;Fluorofenidone;Therapeutic Targets