A型主动脉夹层是心血管系统危急重症。为阐明其分子遗传机制，我们前期对100例A型夹层和94例对照进行全基因组测序，生物信息分析提示TTN基因具有显著突变负担。预实验发现TTN mRNA高表达于人血管平滑肌细胞，故推测其可能为A型夹层易感基因。本项目拟进一步：1）采用目标区域捕获测序技术对易感基因在后续1300例病例、对照样本中进行扩大样本量验证；2）在病例、对照外周血单核细胞及主动脉组织样本中进行TTN mRNA及蛋白表达水平验证；3）在人主动脉血管平滑肌细胞中过表达、敲减TTN，研究其对血管平滑肌细胞增殖、迁移、凋亡等细胞功能的影响。分别构建TTN血管平滑肌特异性过表达、敲除小鼠模型，研究其在组织（主动脉血管环）、整体（动物模型）水平的功能及作用机制。本研究从细胞、组织、整体层面探究了TTN作为易感基因参与A型主动脉夹层发生、发展的机制，为疾病早期预警、早期治疗及改善预后提供理论基础。

Type A aortic dissection is an emergency and severe case of cardiovascular diseases with abrupt onset, rapid progress, and high mortality. In order to uncover its molecular genetic mechanisms, we have performed whole genome sequencing and bioinformatic analysis among 100 type A dissection cases and 94 normal controls. TTN gene was identified to have extremely high mutation burden. Moreover, preliminary experiment indicated that TTN mRNA is predominantly expressed in human vascular smooth muscle cells. Therefore, we hypothesize that TTN may be a potential susceptibility gene for type A aortic dissection. In this project, we intend to: 1)Perform replication study among 1300 cases and controls to validate potential susceptibility gene by using target region capture sequencing technology; 2)Investigate TTN mRNA and protein expression levels both in peripheral blood mononuclear cells and aortic tissue samples of cases and controls; 3)Estimate the impacts on proliferation, migration and apoptosis in human aortic smooth muscle cells through overexpression and knockdown of TTN. Then construct both vascular smooth muscle TTN specific overexpression and knockout mouse models to identify the function and mechanisms of TTN on tissue level (aortic vessel ring) and whole organism level (animal model). The current study investigates functional roles of TTN as susceptibility genes of type A aortic dissection from cell, tissue and whole organism levels and provides novel insights into diagnosis, prevention, prediction, prognosis improvement and personal medication of type A aortic dissection.