银屑病是一种常见且易复发的慢性炎症疾病，世界范围内发病率日趋增高。目前针对银屑病的传统治疗方法都存在一定副作用，而取得较好临床效果的IL-17/IL-23抗体药物费用高昂，使得银屑病治疗面临巨大挑战。因此，寻找靶向精准、副作用小且花费少的小分子药物，极大可能引领当前银屑病治疗的探索方向。.本项目致力于研究可用于银屑病治疗的MALT1新型小分子抑制剂的作用机理。我们前期在《Immunity》报道CARD14点突变小鼠可自发产生银屑病；另外，我们最新发现在此小鼠中特异敲除MALT1可阻断银屑病发病，较敲除IL-23效果更佳。本项目拟利用CARD14点突变小鼠自发模型和咪喹莫特诱导银屑病模型，深入解析MALT1在银屑病发病过程中的作用，系统阐明MALT1蛋白酶活性对银屑病致病的分子机制，并进一步探索MALT1抑制剂用于治疗银屑病药物的可行性，为目前日益紧迫的银屑病治疗提供新的分子靶标和干预策略。

Psoriasis is a common, relapse-prone, chronic inflammatory disease, which affects about two percent individuals worldwide with increasing incidence. While most of drugs can be only short-term used concerning the severe side effects, and even the most effective antibody drugs are costly, such as IL-17 and IL-23 antibody, making it pressing need to develop novel treatment of psoriasis. Therefore, investigating accurate-targeting, less-side-effects and lower-cost small molecule drugs may lead the exploration direction of psoriasis treatment..This project is to investigate the molecular mechanism by which MALT1 is involved in the psoriasis pathogenesis. Our preliminary work published on 《Immunity》 showed that CARD14-E138A gene-mutated mice spontaneously develop psoriasis-like skin inflammation, in which conditional knockout of MALT1 in keratinocytes completely block the pathogenesis of psoriasis, even better than deficiency of IL-23, which may be associated with the enhanced protease activity of MALT1. Therefore, this proposal will focus on the function of MALT1 in the pathogenesis of psoriasis by using spontaneous and Imiquimod-induced psoriasis model, identify and characterize the molecular mechanism how MALT1 protease activity regulates the psoriasis development, determine if MALT1 protease inhibitors can be used as therapeutic agents to treat psoriasis and the mechanism. Together, results from these lines of investigation will provide the molecular insight for designing therapeutic agents against psoriasis pathogenesis.