RNASET2对NB-UVB在黑素细胞双向作用中的影响及在白癜风中的应用价值研究

Narrowband UVB (NB-UVB) could treat vitiligo through a dual effect on inhibiting melanin synthesis and promoting melanocyte apoptosis, while the therapeutic results vary among patients, and this mechanism is still unclear. In the earlier studies, we got following results: 1) for the first time, we reported that RNASET2 was a susceptibility gene for vitiligo; 2) the expression of RNASET2 was increased in skin tissue of patients with poor effect of NB-UVB therapy. We hypothesize that the high expression of RNASET2 could neutralize the dual effect of NB-UVB on the melanin synthesis and melanocyte apoptosis, which is the key factor to determine the curative effect of NB-UVB, and RNASET2 could be a new target to improve the therapeutic effect of NB-UVB. The current project aims: 1) to further confirm the relativity between the expression of RNASET2 in skin tissue and peripheral blood and therapeutic effect of NB-UVB with a bigger samples size; 2) to explore the regulating role of RNASET2 in NB-UVB mediated melanin biosynthesis and melanocyte apoptosis, through zebrafish and cell models with overexpression and knock-out/down of RNASET2; 3) to screen potential drugs that can inhibit RNASET2 expression and improve the treatment of vitiligo. The current project will provide new mechanism and target for the difference of curative effect with NB-UVB.

窄谱中波紫外线（NB-UVB）主要通过促进黑素合成和抑制黑素细胞凋亡的双向作用治疗白癜风，但对不同患者存在疗效差异，其机制尚不清。本课题组前期：1）首次报道白癜风易感基因RNASET2；2）初步发现NB-UVB疗效差的患者皮肤组织中RNASET2高表达。我们提出假说：RNASET2高表达抑制NB-UVB诱导的黑素合成、促进黑素细胞凋亡，是导致NB-UVB疗效差的关键因素，RNASET2可成为改善NB-UVB疗效的作用靶点。本课题拟：1）扩大样本量进一步明确皮肤组织和外周血中RNASET2表达与NB-UVB疗效的相关性；2）通过RNASET2过表达和敲除/敲低的斑马鱼模型和细胞模型，探索RNASET2影响NB-UVB介导黑素合成和黑素细胞凋亡的调控机制；3）筛选抑制RNASET2表达，从而提高NB-UVB对白癜风疗效的潜在药物。本课题为NB-UVB疗效差异提供新机制和治疗新靶点。

研究背景：白癜风发病率近年有上升趋势，目前治疗方法（系统用药、局部用药、光照疗法及自体表皮移植等）效果欠佳。窄谱中波紫外线（NB-UVB）是治疗稳定期白癜风的重要手段之一，但针对不同患者，治疗效果存在很大的差异，其机制尚不明确。本课题组前期首次报道白癜风易感基因RNASET2，并发现NB-UVB疗效差的患者皮肤组织中RNASET2高表达。基于此，深入研究NB-UVB在不同患者中治疗差异的原因，明确RNASET2是否可作为NB-UVB治疗白癜风的疗效预测指标，对实现白癜风个性化精准治疗有重要意义。.研究内容及结果：构建RNASET2过表达的斑马鱼模型和体外三种细胞模型（人原代黑素细胞HEMs、人A2058和鼠B16细胞），首次建立NB-UVB对黑素细胞双向调节的在体和体外模型，并验证RNASET2表达水平与NB-UVB疗效的相关性。斑马鱼在体模型中，NB-UVB诱导的黑素细胞反应性变化的同时伴随RNASET2的过表达，核周聚集增多；RNASET2过表达抑制NB-UVB诱导的黑素合成，促进NB-UVB诱导的黑素细胞DNA损伤、凋亡，破坏其对机体的保护功能。在体外细胞模型中，NB-UVB诱导HEMs、A2058、B16胞内的RNASET2蛋白高表达；RNASET2过表达抑制NB-UVB诱导的HEMs、A2058、B16黑素合成，促进细胞凋亡。进一步研究，我们发现，P53-P21/Bax信号通路的活化介导了RNASET2的促凋亡作用。.科学意义：本课题在人群中研究基础上，在体内、外模型中深入研究RNASET2介导的NB-UVB在不同患者中治疗差异的原因、揭示其分子机制，为NB-UVB疗效差异提供新机制和治疗搜寻新方案，为白癜风个性化治疗提供理论依据。