COL5A2基因突变致主动脉夹层遗传及分子机制研究

Aortic dissection (AD), one of the most urgent cardiovascular diseases, is associated with both high lethality and medical expense. The etiology and pathogenic mechanism of AD is not yet clear. This disease is considered to have a high genetic heterogeneity. Although previous pedigree studies in familial AD have identified some causal genes responsible for this disease, only a small fraction of AD patients can be explained. We performed massively targeted resequencing in all exons with flanking regulatory regions of 152 AD-associated genes in 702 sporadic AD patients and 700 matched healthy controls and found that genes in collagen system account for ~31% patients. Based on our preliminary study, we identified COL5A2 as a novel representative pathogenic collagen encoding gene for AD. In this proposal, we will evaluate the effect of the candidate pathogenic mutations in COL5A2 gene by performing mutant-functional-analysis, and conduct transcriptome sequencing as well as pathway analysis of the aorta tissue of the patients who carried COL5A2 pathogenic mutations. Finally, we will further investigate the potential pathogenic mechanisms of COL5A2-related AD by using COL5A2 knock-out/knock-in rat models and transfected cell models. The study will reveals a pathogenic mechanism of collagen encoding gene and has important value in developing novel therapeutic strategies in patients with AD.

主动脉夹层是最紧急和危重的心血管疾病之一，致死率高，医疗花费高昂，其具体发病原因及致病机制尚不甚明确。该病具有高度遗传异质性，既往的家系研究鉴定出一些致病相关基因，但仅能解释小部分病人。我们对702例散发主动脉夹层病例及700例匹配的正常对照进行152个致病相关基因全部外显子及附近功能调控区域深度靶向测序，发现胶原编码基因突变可解释约31%的病人。在前期研究基础上，我们从胶原基因中筛选出COL5A2这个有代表性的新致病基因。本项目拟对COL5A2的候选致病突变进行突变体功能分析，评估其对COL5A2的功能效应；拟对携带COL5A2致病突变的病人病变主动脉组织进行转录组测序和致病通路分析；拟通过COL5A2基因敲除和敲入大鼠模型、转染细胞模型等工具，探索COL5A2基因突变致主动脉夹层的具体致病机制。通过本项目将明确胶原编码基因在主动脉夹层发病中的一种致病机制，对新治疗策略的开发有重要价值。

主动脉夹层是最紧急和危重的心血管疾病之一，致死率高，医疗花费高昂，其具体发病原因及致病机制尚不甚明确。该病具有高度遗传异质性，既往的家系研究鉴定出一些致病相关基因，但仅能解释小部分病人。我们对702例散发主动脉夹层病例及700例匹配的正常对照进行152个致病相关基因全部外显子及附近功能调控区域深度靶向测序，发现胶原编码基因突变可解释约31%的病人。在前期研究基础上，我们从胶原基因中筛选出COL5A2这个有代表性的新致病基因。本项目评估对比了不同基因突变所致主动脉夹层病人的临床特点和预后，建立了基于基因分型的散发主动脉夹层病人临床预后评估方法。通过对COL5A2的候选致病突变进行突变体功能分析，对携带COL5A2致病突变的病人病变主动脉组织进行转录组测序和致病通路分析，发现突变导致基因表达减低；通过COL5A2和COL5A1基因敲除大鼠模型的研究，发现COL5A2基因突变通过激活TGF-β-SMAD通路导致了主动脉夹层。通过本项目明确胶原编码基因在主动脉夹层发病中的一种致病机制，对新治疗策略的开发有重要价值。项目进展顺利，取得了重要的研究结果，已发表标记资助并见刊SCI论文7篇，分别发表于Science China Life Sciences (IF:4.611)等国际权威期刊上.