特异性抑制ß1肾上腺素受体活性是成功治疗心力衰竭的关键和难点。G-四链体是近年来被广泛研究的一种具有多种生物功能的DNA二级结构。我们发现，在ß1受体启动子中存在一系列保守的G-四链体序列，而配体物Pyridostatin(PDS)能稳定结合其中一种G-四链体，并显著降低ß1受体在心肌细胞中的表达和活性，从而为特异性抑制ß1受体活性提供了一种新思路。本项目拟以该序列的大鼠同源片段Ar26为对象，通过生物物理学手段，解析该G-四链体与PDS作用的结构-功能关系，探讨其在ß1受体表达过程中的作用机理及在临床应用中的价值。具体研究内容包括：确定该G-四链体主要异构体结构及稳定性特征；分析四链体-PDS作用机理及特异性；探索PDS在新生大鼠心肌细胞模型中的生物作用及潜在脱靶效应。本项目将初步阐明该G-四链体与PDS作用的机理，从而为以其为靶位点介入治疗心力衰竭的药物分子设计及临床应用奠定理论基础。

Specific inhibition of ß1-adrenergic receptor (ß1-AR) activity has been regarded as one of the main focuses in the research of heart failure treatment. DNA G-quadruplex (G4) is a kind of DNA secondary structure with various biological functions, which has been intensely investigated in the recent decade. In our preliminary data, we had identified multiple highly conserved G4-forming motifs in the promoter of ß1-AR gene, and demonstrated that ligand Pyridostatin (PDS) can interact with one of the G4s, which significantly inhibits downstream ß1-AR gene expression and activity in rat cardiomyocytes. These findings may provide an alternative genetic approach for the treatment of heart failure. Thus, in this project, by using the homological forming sequence of this G4 in rat (Ar26) as a model, we aim to resolve its structures, and to investigate its biological functions, regulatory mechanisms and therapeutical potentials. Research will be focused on: characterizing the structure and stability properties of the main isoforms of this G4; analyzing biophysical parameter changes in the G4-PDS interaction; and investigating biological functions and potential off-targeting effects of PDS in neonatal rat cardiomyocytes. This research may shed light on mechanisms of G4-PDS interaction in cardiomyocytes and provide theoretical supports in the development of novel genetic ß-blockers.