流感病毒基因组的转录与复制是流感病毒最重要的生理过程，它是由流感病毒自身编码的三个亚基组成的聚合酶复合物来完成。由于传统研究方法的局限性，我们目前对流感病毒聚合酶三个亚基的相互作用关系是怎样影响流感病毒的复制知之甚少。我们前期的工作已经建立了流感聚合酶亚基共进化的计算机模型和深入开展了流感聚合酶的功能研究。在本项目中，我们将提出整合策略系统地分析流感病毒基因复制的结构基础和分子机理。首先，我们将利用实验系统分析流感聚合酶的之间相互作用，并进一步发展计算模型进行数据整合构建流感聚合酶复合物的三维结构。然后，基于构建的结构，我们将通过定点突变和过表达聚合酶二级结构元件系统地探索三个亚基之间的关系对流感聚合酶功能与流感病毒复制的影响。该项目的实施不仅会使我们深入了解流感病毒的复制机理，还将为设计新型的抗流感药物提供重要靶点。

During influenza virus life cycle, the viral gene replication and transcription is an essential process, which is undertaken by RNA dependent RNA polymerase (RdRp). The influenza RdRp is a heterometric complex composed of three subunits, namely PA, PB1 and PB2. Due to the resistance of the complex to structural determination, we have little knowledge about how the interactions between the three subunits affect influenza viral replication. In our previous work, we have carried out computational coevolution analysis of the three subunits and further performed functional analysis of RdRp activity by experiments. In this proposal, we attempt to systematically analyze the structural basis and molecular mechanism of influenza genome replication by using an integrated approach. We first map the interactions within influenza RdRp, which will be interated with the previous knowledge to construct the overall architecture of influenza RdRp. Then we explore the how the interactions between three subunits affect influenza RdRp function and virus replication by mutational analysis and overexpression of peptides derived from interacting interfaces. This study will not only deepen our understanding of molecular mechanisms underlying influenza virus replication but also shed lights into novel targets for influenza therapeutics.