基因组学领域目前存在着三个相互关联且亟需解决的重要问题: (1)如何对由同一个基因利用可变剪接机制产生的不同RNA产物进行准确鉴定； (2)如何对基因表达产物进行准确定量, (3)如何对基因产物与疾病的关联进行研究。问题的根本原因在于: 利用可变剪接，单个基因能够产生多个具有不同结构和功能的RNA。由于产物复杂，人们通常将其当作一个整体而不进行区分。然而，这三个看似简单的问题，实则尚未得到有效解决。针对这三个问题，本项目创新性地提出了从内含子保留的角度，建立多组学数据整合分析方法对其进行解析的思路。通过对基因组、转录组和蛋白组数据的整合分析，对内含子保留进行鉴定，进而提高基因产物鉴定和表达估计的精度；进一步，将内含子保留思路应用于老年痴呆症(AD)的生物标志物及基因靶标的挖掘，研究成果可望为AD药物开发和治疗带来新的思路。项目所提出的方法具有一般性，可望在其他疾病如癌症研究中得到广泛应用。

Currently, three interrelated questions exist in the field of genomics that need to be addressed urgently: (1), how to accurately identify splice isoforms that are produced from the same gene through alternative splicing (AS), (2), how to accurately quantify gene expression by taking into account AS; (3) how to identify associations between gene expression and diseases. These three questions result from the fact that a single multi-exon gene is able to through AS generate multiple isoforms that have different structures and carry different functions. Due to their high complexity, these isoforms are often treated as a single entity without being differentiated. In this project, the idea of utilizing the information of intron retention （IR）, which is a mode of splicing, was proposed to address these questions. We will establish a multi-omic data integrative analysis approach for systematical identification of intron retention and use its information to improve gene annotation and gene expression estimation. Further, we will apply our approach to study Alzheimer’s disease (AD), aiming at discovering novel biomarkers as well as potential gene therapy targets that would be of use for drug development and the treatment of AD. The approach proposed in this project is generalizable, and is expected to be widely used in other fields such as cancer research.