基于表型和靶点互作网络的罕见病药物重定位计算模型研究

项目名称： 基于表型和靶点互作网络的罕见病药物重定位计算模型研究

项目编号： No.61503244

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 自动化技术、计算机技术

项目作者： 赵明珠

作者单位： 上海交通大学

项目金额： 19万元

中文摘要： 罕见病是指患病率很低、很少见的疾病，目前约有7000至8000种，严重影响着人类健康。而由于目标患者少、成本高、周期长等因素，罕见病药物研发速度缓慢，长期以来缺乏有效的治疗和病情控制方案。利用计算生物学方法对现有药物重定位，从中挖掘药物新用途，是较快速解决罕见病治疗困境的可选策略。本项目拟利用网络生物学方法，从现有药物中挖掘出潜在的罕见病用药。首先运用数据整合、文本挖掘等方法，建立关系型数据库，较全面梳理现有罕见病靶点和表型信息。然后基于基因共表达网络、蛋白互作网络和表型聚类，建立罕见病表型和靶点作用关系网络，预测罕见病有关的新靶点。最后利用高通量药物-靶点预测模型，对已知和预测的罕见病靶点进行药物筛选，找出现有药物对罕见病的定向治疗作用。分别从统计检验、分子机理、代谢网络等方面系统阐述预测结果的合理性，为进一步离体和在体试验提供思路。

中文关键词： 罕见病；表型；靶点；基因共表达网络；药物重定位

英文摘要： An Orphan Disease (OD) refers to a rare disease that affects a small percentage of the population. Currently as many as 7000 to 8000 distinct ODs have been confirmed to greatly threaten human health. Due to the small market size, high cost and long cycle, the drug development of OD is at a relatively slow pace, leading to the lack of effective protocol for disease treatment and control. Using bio-computational methods to reposition the existing drugs to novel targets, is an alternative rapid solution to resolve the dilemma of OD treatment. With the help of network biology, this study intends to explore potential drug candidates for OD treatment. Firstly, we will build relational database with comprehensive description of the existing OD targets and phenotypes using data integration and text mining. Then, we will establish target-phenotype networks for OD based on gene coexpression network, protein-protein interactions and phenotype clustering, to predict potential drug targets. Finally, we will use high-throughput drug-target predictive model to screen new drug-target interactions, and reposition the existing drugs for OD targeted therapy. The rationality of the results will be systematically validated with statistical test, and interpreted at the level of the molecular mechanism and the metabolic network. The repositioned drugs may be used as the candidates for further in vitro and in vivo tests.

英文关键词： orphan disease;phenotype;target;gene coexpression network;drug repositioning