纳米疫苗ATRQβ-001防治腹主动脉瘤的机制研究

Abdominal aortic aneurysm (AAA) is one of the deadly diseases among old people.The abnormal activation of AT1R/TLR4 is one of the important mechanisms of AAA.Our team was the first one to develop a ATRQ-001 short peptide vaccine targeted on human AT1R, which had shown good effectiveness in vessel protection in animal models of many diseases, such as hypertension, atherosclerosis, and so on. Our preliminary experiments suggested that AT1R vaccine could effectively inhibit the formation of AAA, and reduce the TLR4 expression in vessels.The contents of this research are listed as below: 1, apply the vaccine on Ang Ⅱ - ApoE - / - AAA mice model before and after the formation of AAA, to verify the role of AT1R vaccine in the prevention and treatment of AAA, and it's effect on PPARγ/AMPK/Egr1 / TLR4; 2, apply the vaccine in vascular smooth muscle cells and macrophages to affect the PPARγ/AMPK pathway, and figure out the mechanism of the vaccine, which can inhibit TLR4 expression and the downstream signal transduction through PPARγ/AMPK EGR1 signal pathway in prevention and treatment of AAA. This research holds promise for providing a new treatment method for AAA, and also elucidate the mechanism of action.

腹主动脉瘤（AAA）是导致老年人死亡的主要疾病之一。AT1R/TLR4的异常激活是AAA发病的重要机制之一。本研究团队在国际上首次研制出针对人AT1R的ATRQβ-001短肽疫苗，动物试验显示对高血压和动脉粥样硬化等疾病表现出优良的血管保护作用。我们的预实验提示AT1R疫苗有效抑制AAA形成，并降低血管TLR4表达。本研究拟：1、利用AngⅡ-ApoE-/--AAA小鼠模型，在AAA形成前、后进行疫苗干预，明确AT1R疫苗对AAA的预防和治疗作用及对PPARγ/AMPK/Egr1/TLR4的影响；2、以血管平滑肌细胞及巨噬细胞为研究对象，干预PPARγ/AMPK通路，研究疫苗通过PPARγ/AMPK/EGR1信号通路抑制TLR4表达及下游信号转导防治AAA的机制。通过本课题的研究，可望为AAA提供新的防治手段，并初步阐明其作用机制。

项目背景：我们的研究团队开发了一种阻止血管紧张素II（Ang II）下游信号转导的短肽疫苗AT1RQβ001。AngII在腹主动脉瘤（AAA）的病理进程中发挥重要致病作用，ATRQβ001疫苗能否防治AAA有待研究。.研究内容和结果：我们使用了两种AAA的经典动物模型作为研究对象（AngII微泵持续灌注ApoE-/-小鼠模型和CaPO4化学损伤C57BL/6小鼠腹主动脉模型），明确AT1RQβ001疫苗是否有效阻止AAA的发生发展，并检测血清和血管壁中炎症因子表达水平，观察血管壁中VSMC表型转化重要标志物。通过AT1RQβ001疫苗及其单抗对AAA相关细胞功能、表型的调控进行研究，阐述AT1RQβ001防治AAA的作用机制。我们的研究结果表明，AT1RQβ001疫苗有效下降小鼠AAA的成瘤率，疫苗或单抗治疗组的动脉瘤直径小于单纯手术组，血管功能得到保护。在免疫组化的观察中发现，AT1RQβ001疫苗组血管平滑肌细胞表型趋向于收缩型，巨噬细胞浸润程度更低。另外，体外实验中发现AT1R单抗有效抑制AngII介导的血管平滑肌细胞分泌OPN。金属基质蛋白酶的表达及其活性均在疫苗的干预下受到限制。.科学意义：ATRQb001疫苗在不同的AAA动物模型中均表现有效的防治作用，并且其效应不完全依赖于降压作用。我们 的研究可能为AAA的防治提供一种新策略。