钠钾ATP酶(NKA)是重要的信号转导体，它与非受体酪氨酸激酶(Src)形成受体复合物(NKA/Src)，通过与强心甾类固醇(CTS)结合，启动信号级联反应，引起心肌肥厚并进一步导致心衰，因而NKA/Src可作为心衰治疗的新靶点。紫珠为固涩正气药，我们的研究显示其活性成分可剂量依赖地拮抗NKA/Src信号通路，抑制心肌细胞的异常增殖，是潜在的天然CTS拮抗剂。本项目拟采用正常及突变的细胞系阐明活性单体对NKA/Src下游信号的调控及基因表达的影响；基于配体与NKA的亲和作用构建其活性成分群的追踪和表征的技术平台，阐明其固涩正气的药效物质；采用野生型和基因敲除动物模型阐明活性部位抑制心肌肥厚的作用机理。本项目从活性单体的机制研究入手，逐步揭示活性成分群、有效部位调控相关信号的作用机制，有助于从分子水平揭示紫珠的性味归经的生物学内涵，也为CTS拮抗剂对心血管疾病的靶向治疗提供新策略及理论依据。

The Na/K-ATPase (NKA) is not only an ion pump, but also an important signal transducer. NKA could bind with the nonreceptor tyrosine kinase (Src) to form receptor complex NKA/Src, which starts the signal transduction pathways through binding with cardiotonic steroids (CTS). This is the significant cause leading to myocardial hypertrophy and further heart failure. NKA/Src is the new target for the treatment of heart failure. Medicinal Callicarpa species are traditional Chinese astringent medicines. Our study showed that the effective substances in Callicarpa kuangdong were potential natural CTS antagonists, which could dose-dependently antagonize the NKA/Src pathway and inhibit the abnormal proliferation of myocardial cells. On the basis of the former study, multiple normal and mutant cell lines would be used to study the influence of the effective substance on regulating and expression of Src downstream signal gene. A technology platform based on the ligand-NKA affinity interaction would be established for the search, separation and identification of the astringent components group in Callicarpa species. Wild type and gene knockout animal models would be used to clarify the mechanism of its inhibition on myocardial hypertrophy and heart failure. This research started with mechanism study of effective substance and used the bottom-up strategy to gradually reveal mechanism of the effective components group and fraction on signal regulating, which would help with elucidating the flavor and meridian tropismon of medicinal Callicarpa species on the molecular level and could provide new strategy and theoretical basis for the targeted therapy of cardiovascular disease through CTS antagonists.