肾素-血管收缩素系统是调控人体血压的重要体系，它的紊乱与高血压等心血管疾病的发生发展密切相关。我们研究组首先发现血管收缩素原(ANT)在血浆中存在氧化和还原两种状态，且血浆中氧化态ANT比例的升高与妊娠期高血压疾病的发生密切相关。最近该发现也被其他研究组所证实。本申请拟利用我们新建立的ANT氧化和还原态检测方法筛选临床样品，系统分析氧化态ANT含量升高与血浆氧化还原体系各成分变化的关系，鉴定出血浆中以及内质网内参与ANT二硫键形成的巯基异构酶，阐明人体ANT氧化态与还原态相互转换的分子机制；分析老鼠血浆中ANT氧还状态与人不同这种种属差异性的原因，探索通过特异性抑制巯基异构酶的活性来调节ANT氧化还原状态的可行性；同时基于新解析的ANT与肾素复合体的晶体结构，筛选并设计可以抑制两者相互作用的小分子化合物，为高血压特别是妊娠期高血压疾病的诊疗奠定基础。

Renin-angiotensin system plays a key role in regulating blood pressure. Abnormality in this system often leads to hypertension which is associated with stroke, renal and heart diseases. We have shown previously that angiotensinogen, the precursor of angiotensin, exists in both oxidized and reduced forms in plasma and the increase in the oxidized form is associated with high blood pressure during pregnancy. Here we intend to elucidate the key mechanism underlying the transition between the oxidized and reduced forms, identify the key thiol isomerases involved in oxidizing angiotensinogen, and investigate why there are differences in the ratio of angiotensinogen in different species. Also based on our newly solved crystal structure of renin-angiotensinogen complex structure, we intend to select and design small molecule compounds to block the interaction between renin and angiotensinogen. This will further our understanding on how human blood pressure is regulated and pave the way for the development of new therapeutic approaches towards hypertension especially pregnancy-induced hypertension.