心肌纤维化的新机制：琥珀酸受体1研究

Myocardial fibrosis (MF) is a common complication of congenital heart disease, and it is a key factor to affect the prognosis of MF. Till now, there are no effective drugs for MF clinical treatment. Therefore, research on the MF pathogenic mechanism, and then finding a new therapeutic target in the MF, has an important clinical significance. In our previous research, it was found that succinate receptor 1 (SUCNR1) gene and protein levels were both significantly high in MF human cardiac muscle and MF derived fibroblasts (FCs) compared to the control and overexpression of SUCNR1 in FCs induced excessive proliferation; using proteome chips and co-immuneprecipitation, screened out the downstream molecule-Smad2. This project aims to confirm the effects of SUCNR1 on MF by checking the fibrosis effects of SUCNR1 on normal or MF mice; after the SUCNR1 overexpression/RNAi, study the effect on FCs proliferation, migration and apoptosis and the molecular mechanism; by regulating SUCNR1 with co-culturing FCs and myocardial cell, study the effect on cardiomyocyte hypertrophy, apoptosis, migration and the molecular mechanism; through inhibition / activation of Smad2, study the SUCNR1 downstream mechanism; verify the role and molecular mechanism of SUCNR1 in human specimens. This project is of great significance for the understanding of MF pathogenesis and development for the new target treatment of MF.

心肌纤维化（MF）是先心病常见并发症，是影响预后的关键因素，但临床上尚无有效治疗MF的药物。研究MF致病机制，寻找治疗新靶标，具有重要的临床意义。本课题组前期发现，琥珀酸受体-1（SUCNR1）差异高表达于MF的人心肌组织和心脏成纤维细胞中（FCs），过表达SUCNR1会致FCs过度增殖；利用蛋白组学芯片及免疫共沉淀技术，筛选出SUCNR1下游分子是Smad2，提示SUCNR1可能通过Smad2导致MF的发生。本课题拟通过体内、体外研究激活/抑制SUCNR1对MF作用及对FCs增殖、凋亡、迁移的影响并研究其分子机制；在SUCNR1过表达/沉默后，分别抑制/激活Smad2，验证SUCNR1作用是否逆转；通过人体标本验证SUCNR1在MF中作用和分子机制；阐明SUCNR1对MF影响及调控机制，确证其在MF中的作用。此项目对于深入了解MF发病机制及开发治疗MF的新靶点具有重要意义。

心肌纤维化（MF）是先心病常见并发症，是影响预后的关键因素，但临床上尚无有效治疗MF的药物。研究MF致病机制，寻找治疗新靶标，具有重要的临床意义。本课题组前期发现，琥珀酸受体-1（SUCNR1,GPR91）差异高表达于MF的人心肌组织和心脏成纤维细胞中（FCs），过表达SUCNR1会致FCs过度增殖；利用蛋白组学芯片及免疫共沉淀技术，反复筛选及验证最后发现SUCNR1（GPR91）下游分子是Smad2-PI3K/Akt，提示SUCNR1（GPR91）可能通过Smad2-PI3K/Akt导致MF的发生。本课题通过体内、体外研究激活/抑制SUCNR1（GPR91）对MF作用及对FCs增殖、凋亡、迁移的影响并发现了其分子机制：Smad2-PI3K/Akt途径；在SUCNR1（GPR91）过表达/沉默后，分别抑制/激活PI3K/Akt，验证了SUCNR1（GPR91）作用逆转；通过人体标本验证了SUCNR1（GPR91）在MF中作用和分子机制Smad2-PI3K/Akt途径；阐明了SUCNR1（GPR91）对MF影响及调控机制，确证了其在MF中的作用。此项目对于深入了解MF发病机制及开发治疗MF的新靶点具有重要意义。