牙周细菌c-di-AMP促进动脉粥样硬化发生发展的分子机制研究

c-di-AMP是细菌中广泛存在的信号分子，调控细菌生长等多种生理功能。前期研究证实牙周致病细菌，如牙龈卟啉单胞菌等可以合成和利用c-di-AMP调节自身代谢和致病毒力。牙周细菌c-di-AMP可诱导高水平的炎性细胞因子，如C反应蛋白、IL-6、TNF-α等，继而可引发血小板的聚集和粘附；且c-di-AMP可以随牙周细菌在血液循环系统异位表达，与血管钙化和动脉粥样硬化风险密切相关。但真核细胞对c-di-AMP的特异性识别机制，及其诱导炎性细胞因子的分子机制有待深入研究。基于以上科学问题，本项目拟通过临床样本、动物疾病模型，结合组织病理学、细胞分子生物学研究，验证以下科学假说：c-di-AMP通过PAMPs模式介导下游生物学效应诱导炎性细胞因子且可以直接作用于VSMC促进血管钙化及动脉粥样硬化。项目研究结果有望丰富牙周微生物与全身疾病关系的理论体系，为牙周炎合并全身慢性病防治提供新的思路。

c-di-AMP is a widely recognized signaling molecule in bacteria, and has physiological functions such as monitoring DNA damage and regulating bacterial growth. Previous studies have confirmed that most periodontal pathogenic bacteria, such as P. gingivalis and Treponema denticola, can synthesize and utilize c-di-AMP to maintain and regulate their energy metabolism and virulences. Periodontal bacterial metabolism is an important factor causing periodontitis. Periodontal bacterial-derived c-di-AMP not only regulates the bacterial growth and metabolism, but also induces high levels of inflammatory cytokines, such as C-reactive protein, interleukin- 1β, interleukin-6, tumor necrosis factor-α, etc. High levels of inflammatory factors can trigger platelet aggregation and adhesion, and are closely related to vascular calcification and atherosclerosis. However, the specific recognition mechanism of c-di-AMP by eukaryotic cells and its molecular mechanism of inducing inflammatory cytokines need further study. Based on the above scientific issues, this project intends to verify the following hypotheses through clinical samples, animal disease models, and histopathology and cell molecular biology studies: c-di-AMP mediates downstream biological effects and induces inflammation through the PAMP model Cytokines promote vascular calcification and atherosclerosis. The project research results are expected to enrich the theoretical system of the relationship between periodontal microorganisms and systemic diseases, and provide new ideas and targets for the prevention and treatment of periodontitis combined with systemic chronic diseases.