动脉粥样硬化（Atherosclerosis，AS）是导致急性心肌梗死、心绞痛等缺血性心血管疾病的主要原因。巨噬细胞作为天然免疫系统中重要的一员在AS发生过程中发挥着关键作用，目前关于泛素化修饰调控AS进展的研究还远不完善。申请者前期发现E3泛素连接酶TRIM31调控巨噬细胞介导的天然免疫反应，相关成果发表在Nat Immunol上。在此基础上，申请者进一步探讨巨噬细胞中TRIM31对AS的调控及机制。申请者首次发现TRIM31可以与清道夫受体LOX-1发生结合，并促进其发生泛素化及降解，抑制巨噬细胞脂质吞噬及相应炎症反应。动物实验证明，TRIM31基因敲除后AS明显加重。我们将利用敲基因小鼠模型、齐鲁医院临床标本、泛素化体系等系统的研究巨噬细胞中TRIM31调控AS的泛素化机制，并筛选小分子先导激动剂。本项研究将进一步完善泛素化修饰调控AS发生发展的分子机制，并为改善AS提供临床药物靶点

Atherosclerosis (AS) is the main cause of acute myocardial infarction, angina and other cardiovascular diseases.Macrophages, as an important part of the natural immune system, play a key role in the occurrence of AS. However, the current studies on the regulation of AS by ubiquitination are far from complete.The applicant previously discovered that E3 ubiquitin ligase TRIM31 regulates the natural immune response mediated by macrophages, and the related results were published in Nat Immunol, a top international journal of immunology.On this basis, the applicant further explored the regulation and mechanism of TRIM31 on AS. We found TRIM31 can bind to scavenger receptor lox-1 for the first time, promote its ubiquitination and degradation, and then inhibit macrophage lipid phagocytosis and the corresponding inflammatory response. Animal experiments showed that AS was significantly aggravated after TRIM31 gene knockout.We will use knockout mouse model, clinical specimens from qilu hospital, ubiquitination system and other systems to study the molecular mechanism of TRIM31 regulating AS through ubiquitination, and screen small molecule lead agonists.This study will further improve the molecular mechanism of ubiquitination and the occurrence of AS, and provide clinical drug targets for the improvement of AS.