两栖类皮肤抗菌肽chensinin-1b抗动脉粥样硬化的分子机制研究

两栖动物皮肤分泌的抗菌肽是先天免疫的重要组成部分，可直接杀灭微生物，并作为免疫调节剂，降低炎症反应。前期研究显示chensinin-1b等多种结构形式的两栖类皮肤抗菌肽可以通过与G-细菌细胞外膜LPS相互作用杀死细菌，并抑制LPS诱导的巨噬细胞TLR4/ MyD88/NF-κB信号通路，同时直接与细胞内模式识别受体NOD相互作用降低炎症反应，调节巨噬细胞的免疫反应，提示这些抗菌肽可在炎症性疾病中发挥独特的作用。动脉粥样硬化是一种慢性炎症性疾病，由脂质代谢失衡和动脉壁内积聚的富含胆固醇的泡沫化巨噬细胞引起的免疫反应失调引起。本项目将研究多种系列两栖类皮肤抗菌肽的NOD-NLRPs及NF-κB抗炎信号通路对泡沫化巨噬细胞中胆固醇摄入与外排及脂质代谢过程的影响，发现其抑制泡沫化巨噬细胞的主要途径，作用靶点及分子生物学机制，为两栖类皮肤抗菌肽成为新型抗粥样动脉硬化药物应用于临床提供理论基

Antimicrobial peptides from the secretions of amphibian skin directly kill bacterial and also reduce inflammatory response induced by lipopolysaccharide (LPS) as the important components of innate immune. Our previous studies have revealed that some antimicrobial peptides isolated and purified from the secretion of Rana chesinensis, including chensinin-1b, kill Gram-negative bacteria via the interaction with LPS, an important component of bacteria cell wall. Importantly, they inhibit the productions of pro-inflammatory factors by TLR4/ MyD88/NF-κB signal pathway and NOD receptor in LPS-induced macrophage, suggesting that these peptides can act on chronic inflammatory disease, such as atherosclerosis, by the mechanism of moderating immunity response. Atherosclerosis is a chronic inflammatory pathological processe in which macrophages produce pro-inflammatory responses induced by oxidized low-density lipoprotein (ox-LDL) and then uptake relatively large of modified lipoproteins there by transforming into foam macrophages. In this present study, we set out to investigate the effects of some antimicrobial peptides from the frog skin secretions, including chensinin-1b, on cholesterol uptake and efflux and regulatory mechanisms of cholesterol metabolism in macrophages by the inflammatory signal pathway, such as NOD-NLRPs and NF-κB. Our research aims at revealing the possible mechanisms of these peptides on inhibiting the foaming macrophage and provides new insights for revealing the potential roles of amphibian skin antimicrobial peptides as new therapeutic modalities using in protecting from atherosclerosis.