GSDMD介导黑素细胞焦亡并调控ILC1参与白癜风发病的机制研究

白癜风是临床中常见的色素脱失性疾病，目前治疗效果仍不理想。近年来研究表明，黑素细胞氧化应激损伤介导固有免疫异常是适应性免疫启动前的重要机制。我们前期研究表明GSDMD依赖型焦亡可能是白癜风黑素细胞损伤新机制，并具有促炎作用。ILC1是新近发现的参与白癜风发病的固有免疫细胞，作为IFN-γ早期重要来源是白癜风重要潜在治疗靶点，但调控机制仍不明确，我们前期研究提示与黑素细胞焦亡的促炎作用相关。本研究拟从临床样本、体外细胞实验、小鼠体内实验三个层面阐明GSDMD依赖型焦亡参与白癜风黑素细胞损伤及其对ILC1的调控机制,并应用新兴技术CRISPR/Cas9、Cre-loxP构建Gsdmd基因敲除黑素细胞及黑素细胞条件性Gsdmd基因敲除/过表达小鼠，以实现对黑素细胞GSDMD依赖型焦亡的特异性研究。本研究不仅揭示白癜风发病新机制，更可为白癜风早期治疗及病情评估提供新思路。

Vitiligo is a common depigmentation disorder due to melanocytes destruction. However, current treatments offer limited efficacy. Recently, innate immunity induced by stressed melanocytes before adaptive immunity activation has been confirmed to be the crucial mechanism in the development of vitiligo. Our previous work suggested that GSDMD-dependent pyroptosis could be the novel mechanism of melanocytes damage. Furthermore, the pro-inflammatory effect of melanocytes pyroptosis may be involved in the regulation of ILC1, which was considered as the initial source of IFN-γ in the pathogenesis of vitiligo.This research aims to investigate the role of GSDMD-dependent pyroptosis in melanocytes injury and its regulation on ILC1 in vitiligo pathogenesis in clinical samples, in vitro and in vivo with Tyr-specific Cre transgenic mice. Notably, the CRISPR/Cas9 technique and Cre-loxP system will be applied in our research to establish Gsdmd knockout melanocytes and melanocyte-specific Gsdmd knockout /overexpression mice to help us study the melanocytes pyroptosis mediated by GSDMD specifically. Our study will not only reveal the unknown mechanism of vitiligo, but also provide potential biomarker to monitor disease activity and therapeutic target for vitiligo in early stage.