利用患者iPSC探索MTHFR基因多态性在主动脉夹层致病机制中的研究

胸主动脉夹层是致死率极高的急重症主动脉疾病，且缺乏预防、早期诊断及预后管理的标志物分子。高血压是胸主动脉夹层的重要诱因，而亚甲基四氢叶酸还原酶（MTHFR）基因多态性导致的同型半胱氨酸代谢异常引起的H型高血压加剧了胸主动脉夹层的风险，但其确切的分子机制尚不明确。前期，我们通过全基因组重测序，首次在胸主动脉夹层患者中发现了MTHFR基因的多态性位点，并且构建了携带该基因多态性位点的患者特异iPSC。本项目将通过研究MTHFR基因多态性对血管细胞的功能影响，建立MTHFR基因多态性与胸主动脉夹层之间的关系，阐明MTHFR基因多态性位点影响疾病进展的分子机制，为临床上针对胸主动脉夹层的早期筛选和预后管理提供理论基础，并可为携带MTHFR基因多态性位点的人群提供胸主动脉夹层致病风险评估和预防策略。

Thoracic aortic dissection (TAD) is the acute and extensive aortic disease with high mortality, which is still lack of specific biomarkers for prevention, diagnosis as well as management. Hypertension has been widely accepted as a risk factor for the contribution of TAD, while the H type hypertension which caused by the abnormality in metabolism of homocysteine significantly increased the pathogenic risk of TAD. During the metabolic cycle of folate and methionine, the abnormal level of homocysteine frequently affected by functional defect of the limiting enzyme methylenetetrahydrofolate reductase as caused by the polymorphism of MTHFR. But, the underlying mechanism of MTHFR polymorphism in the molecular pathopoiesis of TAD still remains uncertain. Previously, the single nucleotide polymorphism of MTHFR was firstly detected in the patients with TAD by whole-genome sequencing and the patient specific iPSC cells, harboring the different MTHFR polymorphism, were also generated. With the specific iPSC derived vascular cells, including endothelial cells and smooth muscle cells, the functional outcomes of the polymorphism were analyzed. Based on the data acquired, the relationship of MTHFR polymorphism and TAD was established. Importantly, the functional SNPs could provide the possibility in early screening and prognosis management, also giving promising perspective in the TAD-risky assessment and precise medication for the carriers with TAD.