ADTRP调控ApoB/Collagen VII/LEPR介导心肌纤维化影响冠心病的分子机制研究

Coronary artery disease susceptibility gene ADTRP is a protective factor of atherosclerosis and plays an important role in the molecular mechanism of coronary artery disease. Previous studies by the applicants showed that ADTRP regulates the expression of target genes ApoB, LEPR and Collagen VII, and together with the target gene MIA3 constitutes a new pathway for the pathogenesis of coronary artery disease, which is composed of ADTRP-PIK3R3-AKT activating MIA3/TANGO1 and Collagen VII/ApoB. However, the mechanism of ADTRP regulating ApoB and Collagen VII mediated myocardial fibrosis and participating in coronary artery disease remains to be identified. In this project, Adtrp knockout mice model was used to study the phenotype of myocardial fibrosis, to clarify the structural basis of myocardial fibrosis induced by ADTRP deletion, and then to study the molecular mechanism of ADTRP regulation of ApoB, LEPR and Collagen VII by cellular, molecular and biochemical means. This study will reveal the molecular mechanism of ADTRP mediated myocardial fibrosis leading to the occurrence and development of coronary artery disease from the individual-tissue-cell-molecular level, aiming to reveal the pathogenesis of coronary artery disease, it provides a new theoretical basis for the clinical prevention and treatment of coronary artery disease and other diseases.

冠心病易感基因ADTRP为动脉粥样硬化的保护因子，在冠心病致病分子机制中起重要作用。申请者前期研究表明ADTRP调控靶基因ApoB、LEPR、Collagen VII表达，与靶基因MIA3共同组成一条冠心病致病机制的新途径；其由ADTRP-PIK3R3-AKT激活MIA3/TANGO1及Collagen VII/ApoB组成。然而，ADTRP调控ApoB及Collagen VII介导心肌纤维化，参与冠心病的机制尚待鉴定。本项目拟利用Adtrp KO小鼠模型，研究其心肌纤维化表型、明确ADTRP缺失导致心肌纤维化的结构基础，再通过细胞、分子、生化手段研究ADTRP对ApoB、LEPR、Collagen VII调控的分子机制。本课题将从个体-组织-细胞-分子层面，揭示ADTRP介导心肌纤维化导致冠心病发生发展的分子机制，旨在揭示冠心病的发病机理，为冠心病等疾病的临床预防与治疗提供新的理论基础。

ADTRP为冠心病易感基因，抗动脉粥样硬化，是保护因子，在冠心病致病分子机制中起重要作用。申请者前期研究表明ADTRP调控靶基因ApoB、LEPR、Collagen VII表达，与靶基因MIA3共同参与一条冠心病致病机制的新途径，其由ADTRP-PIK3R3-AKT激活MIA3/TANGO1及Collagen VII/ApoB组成。然而，ADTRP调控ApoB及Collagen VII介导心肌纤维化，参与冠心病的机制，需进一步鉴定。本项目首先通过体外血管内皮细胞EA.hy926和HepG2细胞发现ADTRP与ApoB/Collagen VII/LEPR相互调控，形成一个正向调控环路；敲低ADTRP和ApoB/Collagen VII/LEPR，导致炎症粘附分子ICAM-1、VCAM-1、E-Selectin、P-Selectin的上调，进一步研究发现ADTRP与ApoB/Collagen VII/LEPR相互调控，共同参与NF-κB p65信号通路，调节与动脉粥样硬化直接相关的内皮细胞功能，从而对动脉粥样硬化提供潜在的保护机制。以上研究成果，从个体-组织-细胞-分子层面，初步揭示了ADTRP调控ApoB/Collagen VII/LEPR介导心肌纤维化影响冠心病的分子机制。