DBC-1上调TNF-α信号促进心梗/再灌后心室重构的作用和机制

项目名称： DBC-1上调TNF-α信号促进心梗/再灌后心室重构的作用和机制

项目编号： No.81470393

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 范慧敏

作者单位： 同济大学

项目金额： 75万元

中文摘要： 心力衰竭是心肌梗死后患者主要致死原因。最新研究表明，心梗后即使血流动力学正常，心肌细胞凋亡仍持续发生并与心室重构严重程度密切相关，而TNF-α信号激活和上调是凋亡关键。本团队研究发现，乳腺癌缺失基因-1（DBC-1）通过增强TNF-α信号，激活下游p38-casepase8通路促进凋亡,因此推测DBC-1通过TNF-α-p38-casepase8通路促进心梗后心肌细胞持续凋亡及心室重构。本课题拟使用DBC-1基因敲除小鼠，不同条件下培养原代心肌细胞，体外评价DBC-1在细胞凋亡中作用；建立DBC-1基因敲除小鼠心梗/再灌注模型，使用p38及casepase8抑制剂，组织学和影像学评价心室重构程度，免疫组化及western blot检测DBC-1及TNF-α下游通路各蛋白表达水平，探讨DBC-1影响TNF-α-p38-casepase8通路参与心室重构作用和机制，为心衰防治提供新策略。

中文关键词： 乳腺癌缺失基因-1；肿瘤坏死因子-α；心肌梗死/再灌注；心室重构；凋亡

英文摘要： Heart failure is the leading cause of death after myocardial infarction. Recent study revealed that cardiomyocytes undergoing persistent apoptosis and closely related to left ventricular remodeling after MI/R, even though the haemodynamics in infarction area comes back to normal. Accumulating evidences have proved that TNF-α signals are the key factors of cardiomyocytes apoptosis. Our former research uncovered Deleted in brease cancer-1(DBC-1) promotes cell apoptosis through up-regulating TNF-α signaling to activate the p38-casepase8 signal pathway, thus accelerating apoptosis. We speculate that DBC-1 may aggravates ventricular remodeling after MI/R via up-regulating TNF-α-p38-casepase8 pathway. To prove the hypothesis, we firstly isolate myocardial cells from DBC-1 wild type and knockout mice and stimulate them with hypoxia, and evaluate the role of DBC-1 in myocardial cells apoptosis by detecting the expression of TNF-α, other inflammatory cytokines, chemokines, systolic function, and apoptosis level; Myocardial infarction/ reperfusion models will be established in each group, and some groups will be treated with p38 and/or casepase8 inhibitor. Through analyzing the degree of ventricular remodeling by histology and imaging, detecting the levles of DBC-1 and TNF-α, and evaluating the state of activation of downstream signal pathway by immunohistochemistry and western blot, we can reveal the mechanism in which DBC-1 promotes cardiomyocytes apoptosis and aggravates ventricular remodeling after MI/R via TNF-α signaling. This project would provide new evidence for the therapy and intervention of left heart faliure after MI/R in clinic setting.

英文关键词： Deleted in Breast Cancer-1;Tumor Necrosis Factor-α;Myocardial Infarction/Reperfusion;Ventricular Remodel;Apoptosis