房室管和流出道内皮间质转化（EMT）是心脏瓣膜形成的关键步骤；HIF1、NFATc1可通过调控VEGF影响EMT过程。我们前期发现：KCTD10敲除小鼠胚胎产生房室瓣缺陷等发育障碍，E9.5和E10.5房室管EMT受到抑制；脐静脉内皮细胞中敲低KCTD10后EMT下游基因β-Catenin和α-SMA表达下调，NFATc1表达减少、HIF1α和VEGF表达增加；KCTD10可结合HIF1β、NFATc1，正调控NFATc1、负调控HIF1α和HIF1β。因此推测KCTD10通过VEGF影响EMT过程而调节心脏瓣膜发育。本研究拟建立内皮细胞、心肌细胞特异剔除KCTD10小鼠，分析KCTD10在心脏瓣膜发育、EMT和VEGF相关通路调节中的作用，利用体外实验进一步分析KCTD10对小鼠胚胎心内膜垫EMT能力、内皮细胞功能的影响及分子机制，研究KCTD10突变与心脏瓣膜病的临床相关性。

The cellular process of Endothelial-mesenchymal transition (EMT) in the atrioventricular canal (AVC) and outflow tract (OFT) are critical events in development of the heart valve；NFATc1, HIF1 affects the EMT by regulating VEGF signaling. Previously, we found that KCTD10 knockout mice show severe defects in atrioventricular valve development, the EMT process at E9.5 and E10.5 were repressed; knockdown of KCTD10 in HUVEC cells cause down-regulation of downstream target genes of EMT such as β-Catenin and α-SMA, decrease of NFATc1, and increases of HIF1α and VEGF; KCTD10 could bind to NFATc1 or HIF1β which positively regulates NFATc1 and negatively regulates HIF1α and HIF1β, respectively. Thus, it is supposed that KCTD10 may regulate the heart valve formation by affecting the process of EMT via VEGF signaling. In this study, we will create mice lines with KCTD10 knockout specifically in endocardiac cells or myocardiac cells; using these mice lines, we will analyze the role of KCTD10 in heart valve development, in the process of EMT and VEGF signaling regulation; we will further check in vitro how KCTD10 knockout affects the EMT process of mice embryonic endocardiac cushion, the function of endocardiac cells, and investigate the underlying molecular mechanism; we are also going to discover the clinical relevance between KCTD10 mutation and valvular heart diseases.