Fibronectin组装在克罗恩病相关肠纤维化中的作用和机制研究

肠纤维化引起的肠道狭窄和结构破坏是克罗恩病的重要并发症，其病理学本质是细胞外基质蛋白的过量累积。文献报道和我们的前期研究结果显示，成纤维细胞通过整合素（integrin）组装的纤连蛋白（fibronectin，FN）可促进包括胶原蛋白在内的多种细胞外基质蛋白纤维的组装并维持其结构稳定，而FN组装在肠纤维化过程中的作用尚不明确。为解决此问题，本研究将首先在克罗恩病纤维化及正常的肠道组织中明确FN及相关integrins的表达情况；进而构建药物和微生物诱导的小鼠肠纤维化模型，探索抑制integrin-FN结合和FN-FN相互结合这两个FN组装的必要步骤是否可以预防和治疗肠纤维化；最后构建可模拟不同纤维化水平和结构的体外肠成纤维细胞3D培养模型，动态观察抑制FN组装对细胞形态，运动及构建胶原蛋白网络的影响。本研究直接关注纤维化组织自身的形成调控，旨在为治疗克罗恩病相关肠纤维化提供新思路。

Intestinal fibrosis is a common complication of Crohn’s disease, often leading to intestinal stricture and deformity. Histologically, it is characterized by excessive extracellular matrix deposition. Fibronectin is secreted and then assembled by transmembrane integrins on intestinal fibroblasts and is essential to the assembly and maintenance of many other extracellular matrix protein fibers, including collagen. The role of fibronectin in intestinal fibrosis, however, is not clear. To solve this question, we start by characterizing the expression of fibronectin and related integrins in fibrotic and nearby normal intestinal tissues, then generate mouse models of chemically and bacteria-induced intestinal fibrosis and investigate the prophylactic and therapeutic effect on intestinal fibrosis by inhibiting fibronectin assembly at integrin-fibronectin binding and fibronectin-fibronectin binding levels. Finally, a 3D tissue culture model for intestinal fibroblasts will be built to mimic various levels and architectural aspects of tissue fibrosis. This model serves as an appropriate in vitro model to investigate the effect of fibronectin assembly inhibition on cell morphology, migration and assembly of collagen fiber network. This research focuses directly on the constructive process of fibrotic tissue in order to provide new insights and therapeutic targets for intestinal fibrosis in Crohn’s disease.