内皮细胞源性外泌体介导microRNA靶向TAK1调节皮肤衰老的分子机制

TAK1对维持皮肤稳态非常重要，抑制TAK1活性将导致细胞凋亡的发生，促进皮肤衰老。前期研究工作中，我们发现内皮细胞也参与调节皮肤衰老的过程。我们通过生物信息学方法，从衰老内皮细胞上调表达的miRNA中筛选出22个靶向TAK1活性的miRNA。外泌体可将miRNA传递给靶细胞并影响其功能。因此我们假设，衰老内皮细胞可以通过外泌体介导miRNA靶向调节皮肤成纤维细胞TAK1的活性，促进细胞凋亡，从而影响皮肤衰老的进程。本研究首先将在细胞共培养体系中证实衰老内皮细胞可以通过抑制TAK1活性促进皮肤成纤维细胞的凋亡；然后从衰老内皮细胞外泌体中鉴定2-3个靶向TAK1活性的miRNA，阐明其调节成纤维细胞衰老的分子机制；并通过建立内皮细胞特异性miRNA转基因小鼠模型，进一步验证内皮细胞通过外泌体介导miRNA对皮肤衰老的影响。本研究将为延缓皮肤衰老及皮肤衰老相关疾病的治疗提供新的药物靶点。

Transforming growth factor-β activated kinase 1(TAK1) is very important for maintaining skin homeostasis. Inhibit TAK1 activity will lead to the occurrence of apoptosis, promote skin aging. In our preliminary study, we found that the endothelial cells involved in the regulation of skin aging process. Through bioinformatics, we screened 22 upregulated miRNA targeting TAK1 activity from senescence endothelial cells. Therefore, we assume that the aging of skin fibroblasts can be affected by miRNA of exosomes derived from endothelial cells through targeting TAK1 activity of fibroblasts. At firstly, this study will confirme aging endothelial cell can promote skin fibroblasts apoptosis by inhibiting TAK1 activity; then identify 2-3 miRNA targeting TAK1 activity from exosomes derived from senescence endothelial cells and clarify their molecular mechanisms in aging. At last, through the establishment of endothelial cell-specific miRNA transgenic mice, we further validate endothelial cells influence skin aging through miRNA of its exosomes. This study will provide new drug targets for delaying skin aging and skin aging-related diseases treatment.