RNA结合蛋白SAMD4靶向FGF2/FGF18维系心肌细胞分化通路的研究

心肌细胞分化命运的时空动态调控是一个重要的科学问题，但是涉及的信号通路如何由RNA结合蛋白介导知之甚少。我们分析发现：RNA结合蛋白SAMD4在人类/小鼠胚胎干细胞定向心肌细胞分化的阶段转换过程中，呈现表达差异趋势协同，并呈现了潜在关键驱动基因的特征；此外，SAMD4在小鼠心脏发育早期特异高表达，且潜在靶向FGF2/FGF18；进一步在小鼠心肌细胞分化模型中，敲低SAMD4显著抑制心肌细胞分化。结合他人证据：SAMD4异常可导致小鼠生长受限并抑制mTOR信号通路。我们推测：SAMD4靶向FGF2/FGF18介导PI3K/AKT/mTOR信号通路，从而维持心肌细胞的正常分化。为此，我们拟结合SAMD4敲除小鼠及人/小鼠胚胎干细胞定向心肌细胞分化模型，利用分子、细胞和电生理等实验方法，阐明SAMD4如何调控心肌细胞分化的分子细节，为心脏再生理论和先天心脏病机制提供科学依据。

The spatiotemporal dynamic regulation of cardiomyocyte differentiation fate is an important scientific issue. It is not entirely clear how the signaling pathways involved are mediated by the RNA binding proteins. Our previous study found that the RNA binding protein SAMD4 showed a concordant differential expression during the cardiomyocyte differentiation in human and mouse and the characteristics of key driver genes. In addition, SAMD4, specific and highly expressed in the early stages of cardiac development, could target FGF2/FGF18. The knockdown of SAMD4 could significantly inhibit cardiomyocyte differentiation. Combining previous founding that abnomal SAMD4 resulted in growth restriction and inhibition of the mTOR signaling pathway in mice, we speculate that SAMD4 can mediate PI3K /AKT/mTOR signaling pathway by targeting FGF2/FGF18 to maintaining normal differentiation of cardiomyocyte. Therefore, we will explore the mechanism of SAMD4 in regulation of cardiomyocyte differentiation using molecular biology and others methods in SAMD4-knockout mouse model and the cardiomyocyte differentiation model of human/mouse embryonic stem cell in vitro. We hope this study will provide experimental evidence for the theory of cardiac regeneration and congenital heart disease mechanism.