内质网蛋白44（ERP44）敲除所致心脏发育缺陷及机制研究

Congenital heart defects（CHD）are common diseases harmful to human health. The pathogenesis of CHD is various and complicated. It not only causes great pain to the patient, but also causes a heavy burden to the patient’s family and the society. Endoplasmic reticulum protein 44(ERP44) belongs to the protein disulfide isomerase superfamily and participates in the quality control of protein maturation and regulation of intracellular calcium homeostasis. Recently, we find that deletion of ERP44 leads to defects of heart development in mice, and the main phonotype is CHD due to the abnormal development of the endocardial cushion. However, the roles and mechanism of ERP44 in heart development are totally unknown, especially the mechanism of ERP44 deletion causes heart developmental abnormal. Therefore, the aim of this project is to investigate the roles and mechanism of ERP44 in heart development, especially to explore the mechanisms of ERP44 deletion caused CHD at the level of molecule, cellular, tissue as well as organ using modern biology and gene manipulation technology, and to provide theoretical basis for prevention and treatment of CHD and possible potential targets.

先天性心脏病是一类常见而严重危害健康的疾病，其发病机制多样而复杂，治疗难度大，给患者造成很大痛苦，给家庭及社会造成沉重负担。内质网分子伴侣蛋白（ERP44）属于二硫键异构酶家族，参与蛋白质成熟、质量控制和细胞钙稳态调控。我们最近研究发现，敲除ERP44导致小鼠严重的心脏发育缺陷，主要表现为心内膜垫发育异常型先心病。但是，对于该基因在心脏发育过程中的作用缺乏了解，为什么敲除该基因会导致心脏发育异常更是一无所知。因此，本立项将应用现代生物学以及基因操作技术，从分子、细胞、组织到器官水平上，深入研究ERP44在心脏发育中的作用，探索敲除该基因导致先天性心脏发育缺陷的分子机制，为防治先天性心脏缺陷疾病提供理论基础和可能的潜在靶点。

ERp44直接与肌醇1,4,5 -三磷酸受体1 (IP3R1)的L3V结合，抑制其活性。在本研究中，我们应用现代生物学以及基因操作技术，从分子、细胞、组织到器官水平上，深入研究了ERP44在心脏发育中的作用，探索了敲除该基因导致先天性心脏发育缺陷的分子机制。我们研究发现，敲除ERP44导致小鼠严重的心脏发育缺陷，主要表现为心内膜垫发育异常型先心病和严重的室间隔和瓣膜缺损，ERp44突变体导致胚胎致死；ERp44基因敲除(KO)小鼠体型小，大多数小鼠在出生后早期死亡；Erp44心肌条件性敲除的cTNT‐Cre+/−小鼠与常规敲除小鼠有相似的表型，ERp44fl/fl小鼠心肌ERp44主要控制心内膜垫的形成。进一步的研究表明，ERp44的缺失显著降低垫层细胞的增殖，并损害心内膜间充质转化(EndMT)，从而导致心内膜垫层发育不良。最后，我们发现ERp44直接与VEGFA结合，并控制其释放，而进一步调控EndMT。.我们的研究阐明了ERP44在心脏发育中的作用，揭示了其机制，并为防治先天性心脏缺陷疾病提供理论基础和可能的潜在靶点。通过本项目的实施迄今已发表SCI论文4篇，已被接受的1篇。同时，本项目培养博士3名，硕士2名。

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