基于转录组的腹主动脉瘤治疗药物的筛选策略研究

Abdominal aortic aneurysm (AAA) is a localized dilatation of the abdominal aorta exceeding the normal diameter by more than 50 percent, or the diameter is greater than 3cm. AAA is one of the most lethal cardiovascular diseases. However, currently it is not very clear about the mechanisms by which AAA formation and development. So far, limited methods are available for AAA prognosis and therapy. In recent years, a number of studies have shown that transcriptome can respond the features of samples under various experimental conditions. This implies that transcriptome could provide new ways for drug screening. We previously built the mouse model of AAA and implemented one transcriptome-based strategy for drug screening. Further animal experiments approved that the identified drugs is useful in inhibiting and treating AAA. This means that it is feasible to screen AAA drugs based on AAA transcriptomes. However, current strategy has two major limitations. One is that it did not consider miRNA transcriptome, which is one key component of transcriptome and should be considered. The other limitation is that it did not consider the importance data of transcripts. Based on the above observations, here we presented to integrated miRNA transcriptome and mRNA transcriptome. We then investigated the integrated-transcriptome-based strategy to screen drugs for AAA. We will also predict the key pathways related with AAA therapy. Finally, animal experiments will be performed to confirm the presented strategy. This project will not only provide new candidate drugs and solution strategy for AAA therapy but also provide theory basis for screening drugs for other cardiovascular diseases.

腹主动脉瘤是指腹主动脉壁扩张大于临近部位直径的50%，或者直径超过3厘米，是一种高致死性的心血管疾病。但是关于它的发病机制至今尚不十分了解，也缺乏药物防治的有效方法。已有研究表明转录组能准确反映各种实验条件下的样本特征。这提示，转录组有望为药物筛选提供新途径。我们前期已成功构建腹主动脉瘤小鼠模型，实现了一种基于转录组的药物筛选策略，动物实验证明了所筛选药物的有效性，说明基于转录组筛选腹主动脉瘤治疗药物是可行的。然而，当前策略还存在两个缺陷，一是未考虑miRNA这一转录组重要成分，二是未考虑转录本重要性信息。在此，本课题提出集成包含miRNA在内的转录组和转录本重要性数据，研究腹主动脉瘤治疗药物的筛选策略，并利用生物信息学预测该病治疗相关的关键分子通路，最后通过生物医学实验进行验证。课题将为腹主动脉瘤的治疗提供新的候选药物和解决策略，为其他心脑血管疾病的药物筛选提供借鉴和理论依据。

腹主动脉瘤是指腹主动脉壁扩张大于临近部位直径的50%，或者直径超过3厘米，是一种高致死性的心血管疾病。但是关于它的发病机制至今尚不十分了解，也缺乏药物防治的有效方法。已有研究表明转录组能准确反映各种实验条件下的样本特征。这提示，转录组有望为药物筛选提供新途径。在本课题资助下，我们开发了基于转录组的药物筛选方法，并开发了相应的软件，筛选出柚皮素为腹主动脉壁的治疗药物。动物实验表明，柚皮素具有显著的预防和治疗腹主动脉瘤作用，该结果已获得中国专利（ZL-2013-1-0264289.3）和国际专利（PCT/CN2014/000093），现在已申请美国和欧洲专利。所开发的基于miRNA的药物筛选软件获得“计算机软件著作权”（软著登字第0798438号）。还提出基于转录组的组合药物筛选方法、腹主动脉瘤新基因预测方法，血管功能相关lncRNA预测方法，提出基于微生物的疾病相似度计算方法，并发现腹主动脉瘤和2型糖尿病相似度为负值，为临床观察两者发病率为负相关提供了一种可能的解释。