m6A甲基转移酶METTL3通过调控角质形成细胞影响银屑病的作用及机制研究

银屑病是一种常见的慢性炎症性皮肤病，以角质形成细胞过度增殖和异常分化为主要特征。近年来，表观遗传学调控在银屑病发病机制中取得了较大进展。N6-甲基腺苷 (m6A) 修饰作为RNA修饰中最普遍存在的一种修饰，在多种疾病中发挥着重要作用。我们的前期研究发现，银屑病患者皮损中m6A的修饰水平及其甲基转移酶METTL3在角质形成细胞中表达下降，治疗成功后METTL3的表达量上调。咪喹莫特诱导银屑病模型小鼠皮损中METTL3的表达亦降低。本课题将在前期研究基础上，以METTL3对角质形成细胞的调控作用作为研究切入点，结合体外细胞实验以及m6A甲基化高通量测序，使用角质形成细胞特异性敲除METTL3小鼠制备咪喹莫特和IL-23诱导银屑病样疾病模型，深入探讨METTL3及m6A修饰在银屑病角质形成细胞过度增殖、异常分化及炎症应答中的分子调控机制，为临床中靶向METTL3治疗银屑病提供理论与实验依据。

Psoriasis is a common chronic inflammatory skin disorder characterized by the overproliferation and aberrant differentiation of keratinocytes (KC). In recent years, great progress has been made in understanding the epigenetic regulation in the pathogenesis of psoriasis. As one of the most common RNA modifications, N6-methyladenosine (m6A) plays an essential role in multiple diseases. Our previous study revealed that m6A modification and its associated methyltransferase like 3 (METTL3) were diminished in the KCs within the skin lesions of psoriasis patients, which were enhanced after successful treatment. In accordance, the expression of METTL3 was also reduced in the cutaneous tissues of imiquimod (IMQ)-induced psoriasis-like dermatitis mouse model. Based on the former findings, our herein research focuses on the regulatory effect of METTL3 on KCs by means of in vitro cell experiment, m6A methylation high-throughput sequencing along with IMQ- and IL-23-induced psoriasis-like disease model using KC-specific METTL3-knockout mice in order to explore the molecular mechanism of METTL3 and m6A modification modulation in the hyperproliferation, abnormal differentiation and inflammatory response of psoriatic KCs and to provide theoretical and experimental basis for clinical development of METTL3-targeted psoriasis-treating agents.