IL-6/STAT3信号通路在启动哺乳动物心肌再生中的作用与机制研究

项目名称： IL-6/STAT3信号通路在启动哺乳动物心肌再生中的作用与机制研究

项目编号： No.81500239

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 聂宇

作者单位： 中国医学科学院阜外医院

项目金额： 19万元

中文摘要： 新生小鼠心尖切除15%后21天可完全再生，为研究哺乳动物心肌再生分子机制提供了理想模型。我们前期结果发现：急性炎症在新生小鼠心肌损伤后再生中发挥了关键作用，同时伴随心肌组织中IL-6表达的显著升高和STAT3的磷酸化激活；提示IL-6/STAT3信号通路可能在启动新生鼠心肌再生中扮演了重要角色。本项目拟通过检测IL-6敲除小鼠心尖切除后的再生能力，以及心肌显微注射IL-6重组蛋白对心肌细胞增殖的影响，正反两方面探究IL-6与新生鼠启动心肌再生之间的联系。分离小鼠原代心肌细胞，通过抑制JAK和STAT3的激活，证实IL-6是否通过JAK/STAT3信号通路促进心肌细胞增殖。运用心肌细胞特异敲除STAT3小鼠，功能学水平确认STAT3在新生小鼠心肌损伤后再生中是否发挥了关键作用。本项目旨在通过急性炎症启动心肌细胞中IL-6/STAT3信号这个新视角，为揭示哺乳动物心肌再生的分子机制提供新思路。

中文关键词： 心脏再生；炎症因子；信号通路；心肌再生；细胞增殖

英文摘要： The hearts of 1-day-old neonatal mice can regenerate completely after partial surgical resection (~15% of the ventricular myocardium). It raised an ideal model to study the molecular mechanism during mammalian cardiac regeneration. Our unpublished data show that acute inflammation occurs immediately after neonatal heart injury and might play key role in neonatal mouse cardiac regeneration, with interleukin-6 (IL-6) elevation dramatically and STAT3 activation, the major downstream effecter of IL-6 signaling. We hypothesize that IL-6/STAT3 signaling pathway activated by acute inflammation is the primary mechanism of initiating cardiac regeneration. In this project, we will prove whether IL-6 is required and sufficient to active JAK/STAT3 signaling pathway and initiated cardiomyocyte proliferation in neonatal mice by IL-6 myocardial microinjection and knockout assays. The relationship between IL-6 promoting cardiomyocyte proliferation and stimulating JAK/STAT3 signaling pathway will be studied in vitro by treating primary cardiomyocytes isolated from neonatal mouse hearts with the various combinations among IL-6 recombinant protein, JAK inhibitor (INCB018424) and STAT3 inhibitor (5, 15 DPP). To confirm the role of STAT3 in cardiomyocyte proliferation and neonatal heart regeneration, we will measure ability of cardiomyocyte proliferation and heart regeneration after apical resection in STAT3 cardiomyocyte-specific deletion mice. These results will help us to understand the role of the IL-6/STAT3 signaling in initiating cardiomyocyte proliferation and cardiac regeneration.

英文关键词： heart regeneration;inflammatory factors;signaling pathways;myocardial regeneration;cell proliferation