抑制瘢痕化修复的TGF-β3自复制信使RNA促进腱骨再生及其机制研究

目前，针对肩袖退变损伤术后再撕裂尚无有效治疗方法。研究表明，转化生长因子β3可抑制瘢痕形成，促进腱骨交界区域重建。但TGF-β3作为蛋白药物直接使用受到作用时间及效率限制。本项目通过构建自复制信使RNA，并基于迈克尔加成反应与氢键结合原理构建编码 TGF-β3的sa-mRNA的脂质体/水凝胶体系。通过将sa-mRNA导入细胞质内，促使细胞内持续翻译TGF-β3蛋白，从而持续抑制瘢痕形成并促进腱骨再生。通过本项目的实施，明确sa-mRNA设计、构建及持续翻译相应靶蛋白的分子机理；探讨该体系对其携载的sa-mRNA的保护与调控释放规律；确定TGF-β3sa-mRNA抑制瘢痕形成促进腱骨修复的机制；揭示抑制瘢痕与腱骨交界区域修复重建的之间的内在联系；阐明该体系抑制瘢痕化修复并促进腱骨修复的机制。本课题有望为肩袖退变损伤术后再撕裂提供有效的解决方法。

The occurrence of recurrent tear after rotator cuff injury seriously affects the functional rehabilitation of patients. At present, there is no effective treatment for poor healing and scar formation in tendon bone junction area. Studies have shown that transforming growth factor β3(TGF-β3) can inhibit scar formation and promote reconstruction of tendon-bone junction region. However, the direct use of TGF-β3 as a protein drug is limited by many conditions. This project combines the characteristics of mRNA therapy to construct self-amplifying mRNA(sa-mRNA), and constructs a transmembrane peptide-liposome/gelatin hydrogel system carrying TGF-β3 sa-mRNA based on the principles of Michael addition reaction and hydrogen bonding. By introducing TGF-β3 sa-mRNA into cytoplasm, it can promote the continuous translation of TGF-β3 protein in cells, inhibit scar formation and promote tendon bone regeneration. Through the implementation of this project, the action rule of TGF-β3 sa-mRNA in the system is explored, the inhibitory effect of TGF-β3 on scar repair and the action mechanism of promoting tendon bone regeneration are clarified, and the action mechanism of the system on rotator cuff injury repair in animal models is revealed. This subject is expected to provide new therapeutic ideas and theoretical basis for rotator cuff injury tendon bone regeneration.