拟靶向代谢组学策略筛选动脉粥样硬化LysoPL标记物群及其在泽泻三萜药效研究中的应用

Atherosclerosis is a chronic progressive disease with high prevalence, and is difficult to diagnose in early stage. Lysophospholipids (LysoPL) may play important roles in oxidative stress and inflammatory processes as cell signal transduction factors. Yet, the mechanisms by which LysoPL involve in atherosclerosis disease progression remain to be explored. In our previous study, a variety of plasma LysoPL were dysregulated in atherosclerotic rats, but were changed towards normal after the treatment with Alismatis Rhizoma triterpenes.Therefore, it is necessary to study the change of LysoPL network in the processes of disease progression and medication treatment. To date, there is no bioanalytical method that can specifically characterize and quantify all LysoPL in rat plasma. In the present study, we aim to solve the technical difficulties by using a pseudo-targeted metabolomics approach, integrating the advantages of two different types of mass spectrometry, and profiling all plasma lysoPL in the form of LC-QTRAP-MRM. The established profile will be used for dynamic screening a group of LysoPL that are significantly dysregulated in atherosclerosis and constructing a three-dimensional LysoPL biomarker group. The validated biomarker group will then be used to evaluate the anti-atherosclerotic effects of Alismatis Rhizoma triterpenes. The study results will shed lights on disease biomarker screening, establish new methods for early diagnosis of atherosclerosis, and provide new evidence for clinical use of Alismatis Rhizoma in preventing and treating atherosclerosis.

动脉粥样硬化是慢性进展性疾病，发病率高，早期诊断困难。溶血磷脂（LysoPL）作为一类细胞信号传导因子，参与血管内皮氧化、炎症反应，在动脉粥样硬化形成中的重要作用尚不明确。前期研究发现，泽泻三萜组分可将多数在大鼠动脉粥样硬化模型中显著变化的LysoPL回调至正常水平。因此有必要系统研究LysoPL代谢网络变化与动脉粥样硬化形成和药物治疗的关系。然而，目前尚无特异性表征、定量血浆中所有LysoPL的分析方法。本项目将采用“拟靶向”代谢组学策略，整合两种质谱仪的功能优势，构建基于LC-QTRAP-MRM的LysoPL特征性轮廓谱方法，进而动态筛选并验证动脉粥样硬化形成过程中的差异性LysoPL，建立三维动态LysoPL标记物群，并将其应用于泽泻三萜的药效学研究。研究成果将为疾病标记物的筛选提供新方法借鉴，为动脉粥样硬化的早期诊断提供新手段，为泽泻在防治动脉粥样硬化中的应用提供新依据。

动脉粥样硬化是慢性进展性疾病，发病率高，早期诊断困难。溶血磷脂（LysoPL）作为一类细胞信号传导因子，参与血管内皮氧化、炎症反应，在动脉粥样硬化形成中的重要作用尚不明确。前期研究发现，泽泻三萜组分可将多数在大鼠动脉粥样硬化模型中显著变化的LysoPL回调至正常水平。因此有必要系统研究LysoPL代谢网络变化与动脉粥样硬化形成和药物治疗的关系。然而，目前尚无特异性表征、定量血浆中所有LysoPL的分析方法。本项目采用“拟靶向”代谢组学策略，整合两种质谱仪的功能优势，构建了基于LC-QTRAP-MRM的LysoPL特征性轮廓谱方法对血浆中的LysoPL进行相对定量分析，并对方法进行了全面的验证。随后，利用该方法动态筛选并验证了动脉粥样硬化形成过程中的差异性LysoPL，建立了三维动态LysoPL标记物群。最后，本项目运用机器学习的算法实现了泽泻中三萜类降脂活性成分的预测，并对部分活性成分进行了实验验证。上述研究结果为疾病标记物的筛选提供了新方法，为动脉粥样硬化的早期诊断提供了新手段，为泽泻降脂的药效物质基础提供了科学依据。