可同时调控光老化皮肤胶原和弹性蛋白表达的circCOL-ELNs的验证与调控机制研究

Photoaging and it’s related skin diseases are always hot topic for aging research. The aberrant of collagen and elastin in dermis is it’s fundamental pathological change. Theoretically, the intervention of these aberrant of collagen and elastin could reverse skin photoaging, and the regulation of both changes of collagen and elastin is the ideal intervention method. Unfortunately the existing tools can only manipulate one of the expression of these two important proteins. During our recent study in circCOL3A1-859267, we accidentally found one kind of circRNA, the circCOL-ELNs could regulate the expression of these two proteins at the same time. Bioinformatics analysis suggests it may act as miR-29 sponges and regulate the expression of MMP-1，MMP-3 and CathepsinK via MAPK/ AP-1 pathway. Therefore, we intend to develop a improved CRISPRi , which could avoid the disadvantage and drawback of RNAi and conventional CRISPRi , designing the dCas9-ADAR2 complex targeting circCOL-ELNs to verify their function. The accomplish of this study can not only provide better means to elucidate the mechanism of skin photoaging, but also benefit for developing the small molecules for the prevention and treatment of photoaging and it’s related skin diseases.

光老化及光相关皮肤病影响身心健康，病理基础为胶原和弹性蛋白的改变。通过调控两种蛋白的合成和降解，可干预这些病理过程。现有的调控手段只能单一的针对其中的一种蛋白。我们最近在研究circCOL3A1-859267调控I型胶原蛋白表达（国自然课题）时意外发现，circCOL-ELNs可同时调控光老化皮肤的胶原和弹性蛋白的表达,并通过生物信息学分析发现其可能作为miR-29的吸附海绵，通过MAPK/AP-1通路调控MMP-1、MMP-3和CathepsinK，从而影响光老化皮肤胶原和弹性蛋白的合成与降解。我们拟用改良的CRISPRi技术克服前期研究中发现的RNAi存在的问题，设计靶向circCOL-ELNs的dCas9-ADAR1复合物来验证其功能。如果验证成功，不仅可为光老化及相关皮肤病机制的研究提供更好的手段，且能开发出新型的小分子药物用于其预防和治疗，有重要的理论和应用价值。

光老化及光相关皮肤病影响身心健康，病理基础为胶原和弹性蛋白的改变。通过调控两种蛋白的合成和降解，可干预这些病理过程。现有的调控手段只能单一的针对其中的一种蛋白。本研究我们证实了circRNA-0011129与miR-6732-5p结合后可同时调控光老化成纤维细胞I型胶原蛋白的合成与弹性蛋白的降解，并在小鼠光老化模型中进行了验证。不仅可为深入研究皮肤光老化的机制研究提供更好的工具，且能据此开发基于非编码RNA的更好的小分子药物用于光老化及相关皮肤病的预防和治疗，具有重要的理论和应用价值。