近来研究表明血清代谢物氧化三甲胺（TMAO）增高与心血管疾病发病有关，TMAO可诱导细胞炎症及内质网-线粒体应激，白介素-37（IL-37）可抑制炎症和成骨反应。预实验提示钙化性主动脉瓣疾病（CAVD）患者中血清TMAO水平升高，然而TMAO在CAVD中的作用尚不清楚。本研究拟通过体外实验和小鼠CAVD模型在体实验，运用基因打靶、基因测序、抑制剂及TMAO干预等手段和免疫印迹、免疫染色、免疫共沉淀等方法，从临床、动物、细胞、分子、基因等水平，探索TMAO促进CAVD发生发展的机制和IL-37抑制TMAO效应的机制，拟证明TMAO通过调节内质网-线粒体应激促进CAVD的发生发展，白介素37通过P62及白介素1受体相关激酶调控TMAO所致的内质网-线粒体应激，抑制炎症和成骨反应，防止CAVD进展，为进一步认识CAVD提供崭新理论依据，也为防治该病提供新的辅助诊断评估指标和干预靶点

The recent studies showed that elevated level of trimethylamine-N-oxide (TMAO) in serum was associated with development of cardiovascular diseases. TMAO caused cell inflammation and endoplasmic reticulum-mitochondrial stress. Inflammatory responses and endoplasmic reticulum stress are involved in the progression of calcified aortic valve disease (CAVD) . Our previous studies had shown interleukin-37 (IL-37) can inhibit inflammatory and osteogenic responses in human aortic valve interstitial cells. The preliminary experiments showed that the serum levels of TMAO in CAVD patients are higher than non-CAVD patients. In vitro expriments and CAVD mice models will be performed to investigate the relationship between TMAO and CAVD. Immunoblotting, Immunostaining, Immunoprecipitation and other methods will be used to explore the mechanisms that TMAO causes CAVD. We hypothesize that TMAO promotes the progression of CAVD via modulating endoplasmic reticulum-mitochondrial stress, and IL-37 inhibits the progression of aortic valve induced by TMAO through interaction with IRAK and P62. This would provide a new sight in the pathogenesis of CAVD and attractive potential targets for the prevention, diagnosis and treatment of CAVD.