ADRQβ-004疫苗靶向α1D-AR调节交感神经失衡与改善肺动脉重构的机制研究

肺动脉高压（PAH）是一种以进行性肺动脉重构和持续性肺动脉压力升高为特点的致死性疾病。肺动脉交感神经（SNS）过度激活及紊乱是PAH发生发展的重要机制之一，阻断SNS可抑制PAH进展，但没有针对SNS药物用于PAH的治疗。研究发现，α1D-肾上腺素能受体（α1D-AR）可能是SNS促进PAH进展的核心环节。本团队成功研制针对α1D-AR的疫苗（ADRQβ-004疫苗，专利号：201910528504.3），已被证实诱导高效免疫应答，显著降低PAH模型的右心室收缩压，抑制肺小动脉重构且不影响循环血压。本课题拟研究：ADRQβ-004疫苗靶向肺动脉α1D-AR，阻止其激活并抑制下游通路，改善肺动脉重构；同时通过降低GRK2水平促进β2-AR活性及表达，介导肺动脉舒张。以阐明ADRQβ-004疫苗靶向α1D-AR降低肺动脉高压的作用机制，为肺动脉高压提供新颖的治疗方法。

Pulmonary arterial hypertension (PAH) is a fatal disease characterized by progressive pulmonary vascular remodeling and persistently elevated mean pulmonary artery pressures. The excessive activation and dysfunction of the pulmonary sympathetic nervous system (SNS) contribute to the progression of PAH, blocking SNS effectively resists the progression of PAH. However, at present, no drugs against SNS can be used to treat PAH. Studies have found that α1D-adrenergic receptor (α1D-AR) might be a key for SNS to promote the progression of PAH. Our team developed a vaccine against α1D-AR (ADRQβ-004 vaccine, patent number: 201910528504.3). It has been verified that ADRQβ-004 vaccine could highly induce an efficient immune response. ADRQβ-004 vaccine obviously reduced right ventricle systolic pressure in PAH models, and it meliorated pathological remodeling of pulmonary arterioles with no effect on circulatory blood pressure. Our subject is to investigate the mechanism that ADRQβ-004 vaccine ameliorated pathological remodeling of pulmonary arterioles through blocking α1D-AR, prohibiting its activation and inhibiting its downstream regulators, and ADRQβ-004 vaccine recovered the diastolic function of the pulmonary arterioles by reducing the expression of GRK2, increasing the activity and expression of β2-AR. Our object is to explore the mechanism of ADRQβ-004 vaccine against α1D-AR ameliorating pathological remodeling of pulmonary arterioles and provide a new treatment for PAH.