人类海马体积的多尺度生物组学研究

海马萎缩是迟发型阿尔兹海默症（Late Onset Alzheimer’s disease，LOAD）最典型的早期征象和最重要的病理特征之一。申请人前期研究工作（Brain，2018）发现海马体积受多基因调控，具有较高的遗传度，能够预测LOAD发展进程。然而，哪些基因的遗传变异-DNA甲基化-基因表达通路会影响人类海马体积仍不清楚。本课题在宏观层面拟利用影像遗传多组学的整合分析方法，全基因组水平探索影响海马体积的遗传变异-DNA甲基化-基因表达的生物调控通路，通过比较上述生物通路在LOAD患者与正常老年被试的异同，阐明LOAD患病的神经生物学机制；在微观层面拟利用基因编辑技术在分子及细胞水平对靶通路进行逐步验证。该课题将通过阐明影响人类海马体积的生物学因果调控通路，为LOAD的病因、发病机制及治疗策略研究提供基因靶点及新思路，进而推动LOAD个体化治疗策略的研发。

Hippocampal atrophy is one of the most typical early signs and the most important pathological feature of Late Onset Alzheimer's disease (LOAD). The applicant's previous work found that the hippocampal volume is a polygenetic endophenotype with high heritability, which can be used to predict the LOAD. However, it is unclear that which SNP-DNA methylation-gene expression pathways affect human hippocampal volume. This project aims to apply the imaging genetics integrated multi-omics analysis to investigate the causal genetic variation-DNA methylation-gene expression pathway of the hippocampal volume from the macro aspect. The similarities and differences of the above pathway between LOAD patients and normal elderly subjects is helpful to clarify the neurobiological mechanism of LOAD disease. Morover, from the micro aspect, genetic editing technology was applied to gradually verify at the molecular and cellular level. This project will provide genetic targets and new ideas for the study of the etiology, pathogenesis and treatment strategies of LOAD by clarifying the biological causal pathways of human hippocampal volume, and then promote the development of individualized treatment strategies for LOAD.