基于蛋白组学和代谢组学研究慢性高原病HAPH症的机制及香青兰干预后的作用靶点研究

The main pathological features of chronic mountain sickness(CMS) is hypoxemia, high altitude polycythemia, high altitude pulmonary hypertension. The most seriously affected and the most complex mechanism is the high altitude pulmonary hypertension (HAPH). In recent years our group did a lot of basic research on Uygur medicine Dracocephalum moldavica L(DML) , we found that the extract of DML has therapeutic effects of CMS, and the antihypertensive effect, so we are ready to joint use of proteomics and metabonomics, between the flavonoids of DML treatment group, Nifedipine treatment group,and CMS treatment model group to study on the differential protein in serum and the characteristics of metabolic in serum .In order to explore the contact with differential protein in serum and the characteristics of metabolic in serum ,and to find the specific target molecule metabolites key protein associated with HAPH disease related, to find the Dracocephalum flavonoids on HAPH disease target molecule and the key protein. Study on the pathogenic mechanism of CMS and the mechanism of action of Uygur medicine DML total flavonoids is the innovation of this project research and the key place.It accord with the research concept that “the disease test the mechanism,the drug test the symptom”.Use a combination of both techniques to verify the Uygur drug Dracocephalum of total flavonoids targets, and to explan the drug's mechanism have an important significance.

慢性高原病的主要病理特征为低氧血症、红细胞增殖、肺动脉高压等。而其中影响最严重、机制最复杂的正是高原肺动脉高压症（HAPH）。近些年本课题组对维药香青兰进行了大量的基础研究，在前期研究中，我们发现维药香青兰提取物有治疗慢性高原病的作用，并有降压效果，因此我们拟联合蛋白组学及代谢组学技术，研究慢性高原病大鼠模型组与平原及维药香青兰总黄酮给药组的血清中差异蛋白表达谱及血清特征性的代谢谱，用它们来探索慢性高原病HAPH症血清蛋白表达谱及代谢谱的相关性，寻找与慢性高原病HAPH症相关的特异性代谢物的靶分子和关键蛋白，以及与维药香青兰总黄酮治疗HAPH症相关的靶分子和关键蛋白。综上，研究HAPH症的致病机制及维药香青兰总黄酮的作用机理是本项目研究的创新之处和关键之处，且符合“以症测理,以药测证”的研究理念。运用二者结合的技术，对验证维药香青兰总黄酮的作用靶点，对说明该药的作用机制具有重要意义。

高原性肺动脉高压是一种严重的肺循环疾病，是多种高原性疾病发病的重要因素，严重危害高原地区人民健康。我们前期初步表明香青兰总黄酮可降低高原性肺动脉高压，为了深入研究香青兰总黄酮抗高原性肺动脉高压作用机制，本课题在建立慢性高原病大鼠模型给予香青兰总黄酮干预，发现1.香青兰总黄酮可以显著降低大鼠肺动脉压力、改善大鼠血液血氧饱和度、降低大鼠血液血红蛋白含量。2.香青兰总黄酮可改善高原低氧引起的肺、心脏、大脑等多脏器损伤。3.香青兰总黄酮可降低大鼠血清IL-6、VEGF、EPO、CRP、IGF、AGT含量，Apo-A1、Apo-C1、Apo-E含量升高。4.采用iTRAQ蛋白质组学技术分析血清差异蛋白，结果显示，与正常组相比，模型组大鼠血清样本中发现了31种蛋白；与模型组比较，香青兰血样本中发现了48种差异蛋白，并对这些差异蛋白进行富集分析。5.采用核磁共振代谢组学技术探究血清内源性差异代谢物变化，共筛选鉴定20种差异代谢物，涉及10条代谢通路。6.通过本项目的实施，共发表论文4篇，培养硕士研究生3人。