miR-146a在UVA诱导皮肤成纤维细胞光老化中作用机制的研究

长波紫外线（UVA）照射所致的细胞老化是人类皮肤受外源环境影响产生衰老的最主要因素。miRNAs对外源环境非常敏感，是机体适应外界环境的重要调控方式。光老化中 miRNAs是否对UVA照射产生响应并参与调节皮肤细胞对UVA的应激反应是本课题研究的核心，以期发掘能够拮抗UVA导致的光老化的miRNAs。本课题组前期通过UVA照射人原代皮肤成纤维细胞构建光老化模型，筛选出差异表达miRNAs，发现miR-146a与调节紫外线辐射后炎症负调控相关，并推测其能通过调控编码的SMAD4等基因进而调节p21等经典的老化相关蛋白参与细胞的光老化进程，后续工作将着重围绕miRNA146a的靶基因，并用功能实验证实miRNA-146a是通过调控其靶基因的表达来发挥功能。我们也将发掘更多功能性的差异miRNAs及其靶基因，为研发光老化的药物靶点提供理论支持。

Photoaging is cell aging caused by long-wave ultraviolet (UVA) radiation, which is the main cause of human skin aging produced by exogenous environment. How to delay skin photoaging has become an important scientific issue all over the world. As an endogenous non-coding small RNA, miRNAs modulate gene expression through paired binding with target gene sequences and miRNAs play essential roles in cell growth and development. miRNAs are sensitive to environmental change and the expression change of miRNAs is an important manner to adjust to environment. During UVA induced photoaging, it is our center to investigate whether miRNAs are responsive to UVA to participate in the UVA caused stress reaction of skin cells and then to discover specific miRNAs which can antagonize the UVA induced photoaging. The fibroblast of dermis is the main target site of UVA, so we established the in vitro photoaging model with UVA radiated human primary cultured fibroblasts, which was proved to be photoaged. To screen the differential miRNAs in photoaging, we revealed some differentially expressed miRNAs with gene chip, including 5 up- and 8 down-regulated miRNAs, which was verified by qRT-PCR analysis.We found that miRNA146a was correlated with inflammation negative regulation caused by UVA, and then we presumed that it could regulate its target gene SMAD4 and other classical aging associated proteins (such as p21) to participate in photoaging. Sequential work will focus on searching for miRNA146a targets and proving that miRNA146a plays important roles through targeting that target gene. We will also discover more functional miRNAs and their target genes and provide theoretic foundation for developing drug target of photoaging.