紫檀芪纳米制剂通过调控YAP/TAZ-Th17通路在干眼治疗中的应用和机制研究

干眼是最常见的眼表疾病，它的自发性加重以泪液的高渗状态和眼表持续性炎症反应为核心。如何有效提高泪液的稳定性以及抑制眼表炎症反应是干眼临床治疗面临的巨大挑战，而药物治疗的难点在于药物需要同时具备适合眼表应用的理化性质和明确的抗炎靶点。本团队前期研究显示紫檀芪（PS）有良好的抗氧化和抗炎性能，且具有潜在的调控YAP/TAZ-Th17通路作用，是良好的备选药物。但由于其脂溶性和易氧化的特点，难以进一步应用于临床。本项目拟通过构建纳米药物载体，合成PS-多肽双亲性化合物（PS-GA-RGD），以解决其水溶性和稳定性差的问题。其次，构建人角膜上皮细胞高渗模型和小鼠干眼模型，证实其治疗干眼的安全性和有效性。最后通过研究YAP，TAZ等基因和蛋白表达水平，并进行相应的过表达和敲减，来进一步阐明其通过调控YAP/TAZ蛋白表达，调节Th17细胞的分化，抑制眼表炎症的分子机制，以期为干眼的治疗提供新策略。

Dry eye is the most common ocular surface disease, and its spontaneous aggravation is centered on the hyperosmotic state of tears and persistent ocular surface inflammation. In clinic, it’s a great challenge to improve the stability of tear film effectively and inhibit ocular surface inflammation in dry eye treatment. And the difficulty of drug therapy is that drugs need to have both physiochemical property and specific anti-inflammatory targets suitable for ocular surface application. In our previous study, we have found that pterostilbene (PS) has potent antioxidant and anti-inflammatory properties, and has a potential role in regulating YAP/TAZ-Th17 pathway, which showed as a good drug candidate. However, because of its fat solubility and strong oxidability, it is difficult to be further applied in clinic. In this project, amphiphilic nanomedicine of PS- peptides (PS-GA-RGD) were synthesized by constructing nano-drug carriers to improve its poor water solubility and stability. Then we construct hyperosmotic human corneal epithelial cell model and dry eye murine model to confirm safety and efficacy of PS-GA-RGD in the treatment of dry eye. Finally, we detect the mRNA and protein expression levels of YAP, TAZ in different conditions (i.e. overexpression, knockdown), to further clarify its molecular mechanism of inhibiting ocular surface inflammation through regulating YAP/TAZ protein expression and Th17 cell differentiation. The research results will lay a foundation for dry eye treatment and provide a new strategy.