VDR-DBD介导的毛囊细胞过度自噬及周期功能障碍在休止期脱发中的致病机制及靶向治疗研究

项目名称： VDR-DBD介导的毛囊细胞过度自噬及周期功能障碍在休止期脱发中的致病机制及靶向治疗研究

项目编号： No.81673075

项目类型： 面上项目

立项/批准年度： 2017

项目学科： 医药、卫生

项目作者： 赵恒光

作者单位： 重庆医科大学

项目金额： 25万元

中文摘要： 休止期脱发包括雄激素性脱发和斑秃等，占皮肤科脱发门诊90%以上。目前其发病机制不清，治疗手段有限。他人和我们的前期研究均表明，VDR在毛囊周期中呈动态表达，VDR及下游信号异常将导致毛囊干细胞和毛母质细胞的储备、增殖和分化障碍，引起休止期脱发；同时发现VDR通路异常后毛囊干细胞和毛母质细胞中DDIT4表达增加，自噬相关蛋白LC3-Ⅱ/Ⅰ上调，而cyclinD1下降。因此推测VDR通过DBD域负性调控DDIT4的表达，从而抑制mTORC1通路，导致细胞周期转化障碍并激发过度自噬，毛囊持续处于休止期。本课题将在前期基础上，继续深入研究VDR-DBD负性调控DDIT4的机制、对mTORC1通路的调节作用及对毛囊细胞周期和自噬的影响，以及靶向干扰VDR-DDIT4-mTORC1通路对临床休止期脱发的治疗作用，不仅为进一步揭开临床休止期脱发的发病机制提供新认识，也为研发特异性靶向治疗药物提供新方向。

中文关键词： 休止期脱发；自噬；细胞周期；维生素D受体；雷帕霉素受体

英文摘要： Telogen effluvium, mainly including androgenic alopecia and alopecia areata, was responsible for more than 90% in dermatologic hair-loss clinics. Currently, its pathogenesis remains unclear and treatments are ineffective. Preliminary studies from others and ours found VDR plays a key role in the pathogenesis of telogen effluvium. The VDR-DBD congenital mutation or artificially knocked out mice will induce telogen effluvium, with the dysfunctions of reserve, proliferation and differentiation of both hair follicle stem cells and hair matrix cells. Once VDR-DBD impaired, DDIT4 continuously elevates and lose its dynamic cycle, along with increased expression of autophagy-related proteins LC3-Ⅱ/Ⅰ, but decreased expression of cyclin D1. It suggests the genetic or environmental factors probably induce the telogen effluvium through the over-activated autophagy and dysfunction of cell cycle transformation by VDR-DBD-mTORC1 pathway. To further study this hypothesis will not only contribute to uncover the exact pathophysiology of telogen effluvium, but also benefit to develop a novel targeting therapies for telogen effluvium through VDR-DBD-DDIT4-mTORC1- autophagy/cell cycle” pathway.

英文关键词： telogen effluvium;autophagy;cell cycle;vitamin D receptor;mTOR