血管内皮细胞FKBP11调控单核巨噬细胞表型转化的分子机制及其在主动脉夹层防治中的作用

Aortic dissection (AD) is a potentially fatal vascular disease, because of its complexity in etiology effective therapeutic strategies are still lacking. Recently we have identified vascular endothelial FKBP11 gene as a key player in AD formation and progression by transcriptome analysis. In the current study, we will firstly establish an arterial endothelial cell specific FKBP11 knock out mouse line, and subsequently we will use this mouse line and in vitro experiments to further explore the mechanism by which vascular endothelial FKBP11 gene regulates phenotype shifting of the mononuclear phagocyte system via a Notch dependent signaling pathway,and in the meanwhile the clinical patient samples will be collected to verify our findings. Finally, an improved CRISPR-Cas9 technology will be applied to suppress the vascular endothelial FKBP11 gene expression in a mouse AD model, its clincal and translational potential will be estimated. In summary, our current study will provide new thought and precise therapeutic strategy in the field of AD.

主动脉夹层（AD）是一种具有潜在致命性的血管性疾病。其具体致病机制仍不明了，因此有效防治方案尚缺失。我们前期通过转录组学分析明确了血管内皮细胞FKBP11基因同AD发生发展相关，但其具体分子机制仍不明了。本课题将首先建立FKBP11动脉血管内皮细胞特异性敲除小鼠，然后运用上述小鼠及离体细胞实验阐明内皮细胞FKBP11是如何通过Notch信号通路来调控单核巨噬细胞表型转化从而参与AD发生发展的，并收集人体标本予以验证。最后采用改良的CRISPR-Cas9在体基因编辑技术验证内皮细胞特异性下调FKBP11基因的表达对AD的保护作用，为AD的精准防治提供新的理论依据。

主动脉夹层(AD)是一种危急的心血管疾病，其具体发病机制尚不明了，仍缺乏有效的防治手段。为了明确AD发病机制，我们首先通过荟萃分析和动物实验的方法确立了稳定可靠的小鼠AD模型。随后，通过建立人AD生物样本库和小鼠AD模型，我们发现AD组血浆及血管组织中FKBP11表达较对照组显著升高，且血管平滑肌细胞（VSMC）FKBP11的表达较其他细胞升高更明显。此外，通过动物实验和相关细胞实验，我们发现内质网应激（ERS）在AD发生时被显著激活，运用ERS关键效应蛋白IRE1α激酶抑制剂可以通过减少FKBP11的表达，抑制VSMC从收缩型向分泌型的表型转换并降低其凋亡从而对AD起保护作用。为了进一步阐明FKBP11参与AD发病的具体分子机制，我们利用CRISPR-Cas9基因编辑技术成功构建FKBP11敲低的稳转VSMC，并通过转录组测序及生物信息学分析得到潜在靶点及信号通路，并通过qPCR进行验证。该研究为AD的精准防治提供新的理论依据。