内源性多肽PDTLN1致胚胎心脏发育畸形的作用机制研究

PDTLN1 is a novel endogenous peptide of unknown function that is conserved in multiple species (e.g.,human,rat,mouse, zebrafish), and is highly expressed in myocardial tissue and maternal peripheral blood of aborted fetuses with heart malformation identified by peptidomics techniques. We previously found that overexpression of PDTLN1 inhibited cardiac differentiation of P19 cells,and overexpression of PDTLN1 in zebrafishembryos induced cardiac malformation. Furthermore, TLN1 of PDTLN1 precursor protein was reported to involve in the heart development by regulating the Integrin β1. High-throughput screening and verification test shows that overexpression of PDTLN1 in P19 cells activated the Integrin β1 and its downstream GSK-3β/β-catenin signaling pathway. These results suggest that PDTLN1 may induce embryonic heart malformations by regulating Integrin β1signaling pathway. Based on these data, we propose to analyze the temporal expression pattern and function of PDTLN1 during cardiac differentiation and development. In addition, we take Integrin β1 signaling pathway as the clue and analyze the interaction between PDTLN1 and Integrin β1signaling pathway, which will explore the mechanism of PDTLN1-induced cardiac malformations in embryos. The effect and mechanism of PDTLN1 is clarified in embryonic heart development, which will potentially provide a new target for the prevention and treatment of fetal congenital heart disease.

PDTLN1是我们借助多肽组学发现的、不同物种（人、大鼠、小鼠、斑马鱼）间高度保守、同时高表达于心脏发育异常流产胎儿心肌组织和胎儿母外周血中、功能未知的一条内源性多肽。前期发现：PDTLN1干预不仅致斑马鱼心脏发育畸形，而且显著抑制P19细胞向心肌样细胞的分化；已报道，PDTLN1的前体蛋白TLN1与心脏发育有关并能调控整合素β1，而高通量筛选并验证显示，PDTLN1干预时，P19细胞中整合素β1及其下游GSK-3β/β-catenin信号通路也明显激活，提示PDTLN1可能通过调控整合素β1信号通路而影响胎儿心脏发育。研究拟深入分析PDTLN1在心肌分化和心脏发育中的作用；并以整合素β1信号通路为线索，论证PDTLN1参与整合素β1信号通路、调控心肌分化和心脏发育的具体机制。阐明这一功能未知的多肽PDTLN1在胚胎心脏发育中的作用及机制，可能为先天性心脏病在妊娠期的早期防治提供新靶标。

PDTLN1是我们借助多肽组学发现的、不同物种（人、大鼠、小鼠、斑马鱼）间高度保守、同时高表达于心脏发育异常流产胎儿心肌组织和胎儿母外周血中、功能未知的一条内源性多肽。研究发现：PDTLN1干预不仅致斑马鱼心脏发育畸形，而且显著抑制P19细胞向心肌样细胞的分化；PDTLN1通过抑制PI3K/AKT信号通路，导致斑马鱼胚胎心脏发育缺陷，抑制细胞活力，抑制细胞增殖，促进P19细胞凋亡。阐明这一功能未知的多肽PDTLN1在胚胎心脏发育中的作用及机制，可能为先天性心脏病在妊娠期的早期防治提供新靶标。