miR-431及其相关信号通路在心肌纤维化中的作用

Cardiac fibrosis is characterized by excessive accumulation of extracellular matrix due to unbalanced proliferation and activation of cardiac fibroblasts, which is involved in most kinds of cardiovascular diseases. Dysregulation of microRNAs (miRNAs, miRs) is associated with cardiac fibrosis. Previous work of our research team uncovered a pro-fibrogenic miRNA miR-433 in cardiac fibrosis. Our preliminary experiments on miR-431, which is clustered with miR-433, demonstrated that miR-431 was elevated in fibrogenic activated cardiac fibroblasts and fibrotic myocardium. Additionally, it exhibited a pro-fibrogenic effect on fibrogenesis of cardiac fibroblasts. We also found out an upstream regulator SNAI2 and a potential target gene Kremen1 of miR-431. In this project, we plan to conduct gain-of-function and lost-of-function assays of miR-431 in activated cardiac fibroblasts and in mice post-myocardial infarction and angiotensin-induced myocardial fibrosis model to clarify the role of the miR-431 in cardiac fibrosis. Moreover, we will explore the underlying mechanism of miR-431-mediated cardiac fibrosis by means of in vitro and in vivo rescue experiments. Targeting miR-431 and its related regulators may be a potential solution for prevention and treatment of fibrotic heart diseases.

心肌纤维化与多种心血管疾病的发生发展密切相关，miRNA的失调与心肌纤维化相关。课题组早先发现miR-433促进心肌纤维化，我们的前期研究结果显示miR-433同家族的miR-431在心肌纤维化时显著增加，其在细胞水平可以促进心脏成纤维细胞的增殖和向肌成纤维细胞转化。我们还初步发现SNAI2是它的上游调控因子，而Kremen1是它的下游靶基因。在本项目中，我们拟基于大鼠心脏成纤维细胞和小鼠心肌梗死后重构和血管紧张素II诱导重构模型，进行miR-431的功能获得性和缺失性实验，明确miR-431对心肌纤维化的调控作用。在此基础上，通过体内外功能挽救实验，明确miR-431的靶基因和上游调控因子。本项目将阐明miR-431及其相关信号通路在心肌纤维化中的作用，抑制miR-431有望成为新的心肌纤维化防治靶点。

心脏纤维化的特点是由于心脏成纤维细胞的失衡增殖和活化导致的细胞外基质的过度堆积，与大多数心血管疾病有关。 microRNAs的失调与心脏纤维化有关。本研究的结果表明 miR-431 在纤维化活化的心脏成纤维细胞和纤维化心肌组织中升高。此外，我们发现 miR-431 对心脏纤维化表现出促纤维化作用。 miR-431的拮抗作用在体外抑制了心脏成纤维细胞的纤维化活化，在体内抑制了心肌梗死诱导的心肌纤维化。此外，我们还在心脏纤维化过程中鉴定出了 miR-431 的上游调节因子 SLUG和靶基因Kremen1。总之，本项目的研究结果表明 miR-431 通过靶向 Kremen1 在心脏纤维化中起关键作用，miR-431 的拮抗是治疗和防治心脏纤维化的潜在策略。

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