α1A肾上腺素能受体短肽降压疫苗研究

The effect of alpha1-adrenergic receptors blockers is remarkable in treating hypertension clinically. However, because of the complication of the subtypes and the short time of the half-life, the blocking effect not lasting long ,so they can not protect the target organs effectively and lower blood pressure smoothly.Alpha1A-adrenergic receptor(alpha1A-AR) is the main subtype of alpha1-adrenergic receptors for maintaining and regulating the systemic blood pressure, which is the more specific target for lowering blood pressure. In our previous work, an inhibitive antibody against alpha1A-adrenergic receptor has been successfully produced, the epitope of which is the short peptide in length of 7 amino acid residues locating in the second extracellular loop of the alpha1A-adrenergic receptor(CP-7). The antibody can block the activation of alpha1A-adrenergic receptor effectively in vivo and in vitro, which gives our clues that the epitope(CP-7) may be the potential target of hypertension vaccine. In addition, based on the modified ideal carrier-virus-like particles,we have produced the effective and safe hypertension vaccine- ATRQβ-001,which target the human angiotensin Ⅱ type 1 receptor. This research intends to link the short peptide with virus-like particles of the Q beta bacteriophage. The vaccine will be then immunized into the spontaneously hypertensive rats,phenylephrine-induced hypertensive mice and Wistar-kyoto rats. We will test the production of antibody, measure lood pressure and process morphology analysis to value the effectiveness and safety of the vaccine.We aim to produce a hypertension vaccine which can lower the blood pressure smoothly and safely in a long time, to supply an alternative choice for hypertensive patients..

临床上针对α1肾上腺素能受体（α1-ARs）治疗高血压的阻断剂效果显著，但因α1-ARs亚型复杂且现有阻断剂半衰期短，阻断效果持续性差，不能达到有效的靶器官保护和平稳的降压作用。α1A-AR是对全身血压维持和调节发挥主导作用的亚型，是更特异性高血压治疗靶点。本团队研制出一种抑制性抗α1A-AR胞外第2环短肽（CP-7）抗体，体内外实验证实该短肽抗体有效阻断α1A-AR的活化，提示CP-7极有可能为高血压疫苗靶点；并且，基于改建的理想病毒样颗粒（VLP）载体，本团队已研发出针对人血管紧张素Ⅱ1型受体的有效且安全的ATRQβ-001疫苗。本研究拟：将α1A-AR抗原表位CP-7与VLP耦联制备疫苗，主动免疫自发性高血压大鼠、苯肾上腺素诱导的高血压小鼠以及京都Wistar大鼠，观测抗体产生、血压并进行病理分析，评估该疫苗的有效性与安全性，为高血压联合治疗提供新思路和新方法。

在治疗病人中高血压控制率仅有约33%，这主要与多药联合治疗每日口服等繁杂的服药程序以及药物的不良反应相关。相对于化学药物，治疗性疫苗半衰期较长，特异性较高，可以成为与化学药物互补的治疗手段。α1肾上腺素能受体是交感-肾上腺素能系统生物反应的重要介导者，是治疗高血压的重要靶点。在我们实验中，我们筛选拮抗α1-肾上腺素能受体的短肽，与噬菌体病毒样颗粒偶联后免疫自发性高血压大鼠，评价其在体降压效应以及纯化浓缩特异性抗肽抗体进行体外功能分析。在自发性高血压大鼠动物模型中证实：与单独载体组相比，α1胞外短肽V2免疫组在免疫过程的某个阶段可以显著抑制自发性高血压大鼠血压升高幅度，并与抗体滴度具有显著相关性。后期将进一步进行该疫苗的临床药物试验，进一步评估有效性、安全性，希望为高血压治疗提供新策略。