RGD多肽水凝胶的研制及其在青光眼滤过术后抗瘢痕化的作用机制

The effect of glaucomatous filtering surgery is majorly determined by the proliferation of fibroblast. The key process of fibroblast proliferation involves the activation of integrin which is one of the receptor in the membrane of fibroblast and a series of changing of cell biological behavior which is evoked by the integrin combined with relative lagend.The recognition site between integrin and relative legand is called the RGD peptide, which is a kind of micromolecule including arginine, glycine and aspartic acid. From this subject, a peptide containing a RGD (arginine-glycine-aspartic acid) sequence as well as a hydrophobic N-fluorenyl-9-methoxycarbonyl (FMOC) tail will be prepared via a standard FMOC solid phase peptide synthesis (SPPS) technique. The supramolecular self-assembly of such peptide through π-π stacking from FMOC tail can transfer the peptide aqueous solution into a three-dimensional hydrogel. We expect RGD sequense in the three-dimensional hydrogel can be targetly combined with integrin of the fibroblast, and implement the peptide hydrogel to carry antibolism drug and targetly deliver drug to fibroblast.In this subject, we will study the biological effect in the competition inhibition of fibroblast proliferation and preventing scar formation mechanism of the RGD peptide hydrogel by analysing the activation of signal-pathway and the secretion of cytokines, and discuss drug delivery system constructed by RGD peptide hydrogel.The peptide hydrogel will exhibit a good biocompatibility because the degradation results of the peptide hydrogel is amino acid which can be absorbed by human body. We might synthesize a novel biomedical material which possess the good biocompatibility, this novel biomedical material can successfully prevent the scar formation after glaucomatous filtering surgery.

成纤维细胞增殖产生瘢痕是影响青光眼手术效果的主要原因。成纤维细胞增殖活化的关键环节是细胞膜上整合素的活化并与相应配体结合引起一系列细胞生物学行为改变。整合素和其配体相互作用的识别位点是一类含有精氨酸-甘氨酸-天冬氨酸的小分子多肽, 即RGD多肽。本课题拟从RGD多肽构象及其侧位的残基特性以及自组装行为出发，合成能靶向性地结合成纤维细胞整合素、能承载和缓释抗代谢药物的RGD多肽水凝胶。研究人工合成的RGD多肽水凝胶与整合素竞争性结合在阻断成纤维细胞增殖活化中的生物学效应，通过分析信号通路激活及细胞因子分泌变化，探讨RGD多肽水凝胶及药物控释系统在抑制瘢痕形成中的作用机制。RGD多肽水凝胶最终降解产物对机体无毒副作用，具有良好的生物相容性，材料本身及其构建的药物控释系统能有效抑制青光眼滤过术后瘢痕化。课题可能寻找到一种新型的生物学性能良好的生物医用材料，其应用将在抗青光眼手术中发挥重要作用。

成纤维细胞增殖产生瘢痕是影响青光眼手术效果的主要原因。成纤维细胞增殖活化的关键环节是细胞膜上整合素的活化并与相应配体结合引起一系列细胞生物学行为改变。整合素和其配体相互作用的识别位点是一类含有精氨酸-甘氨酸-天冬氨酸的小分子多肽，即RGD多肽。 . 本课题从RGD多肽构象及其侧位的残基特性以及自组装行为出发，合成能靶向性地结合成纤维细胞整合素、能承载和缓释抗代谢药物的RGD多肽水凝胶。并通过一定的凝胶/液体比例，使小分子RGD 多肽能够自组装成可注射RGD多肽水凝胶。. 研究证实RGD多肽水凝胶，通过调节整合素β1、FAK及Akt信号通路，抑制Tenon’s囊成纤维细胞的过度增殖和炎症因子释放。同时，证实了RGD多肽水凝胶可以抑制巨噬细胞及淋巴细胞的炎症因子分泌及信号激活，以及抑制新生血管的形成。. 将5-氟尿嘧啶、丝裂霉素C及白藜芦醇三种抗代谢药物装载于水凝胶中，构建了RGD多肽水凝胶药物缓释系统，发现其能靶向控释抗代谢药物，具有良好的生物相容性、降解产物无毒副作用，水凝胶具有良好的机械性、柔韧性、降解速率可控（可在1周到1个月间调节）、合适的亲水/疏水比等特点。. 这种新型的生物学性能良好的生物医用材料，将其应用在抗青光眼手术中能发挥重要作用。并且根据其物理、生物特性以及其强大的载药能力，能够延申发展应用到多个学科。