ACTG2新突变位点对巨膀胱-小结肠-肠蠕动不良综合征致病分子机制研究

巨膀胱-小结肠-肠蠕动不良综合征（MMIHS）是严重的平滑肌功能障碍罕见疾病，死亡率高，发病机制不明。研究发现ACTG2突变位点p.R257H/C与MMIHS发生密切相关。我们近期在中国MMIHS患儿中发现了ACTG2的三种新突变位点p.E196D、p.P113S和p.D245G。研究提示ACTG2位点突变可能通过影响肌动蛋白聚合对MMIHS发病起作用，但缺乏体内实验支持，其发生分子机制仍不清楚。为此，本课题将构建ACTG2不同突变位点小鼠，从分子网络、细胞超微结构改变和细胞间关联、组织和动物消化道动力功能多层面水平探究ACTG2突变在MMIHS发病中的具体作用；确定ACTG2如何对平滑肌细胞收缩相关基因的调控；阐明ACTG2不同突变位点影响MMIHS不同临床结局的分子机制，为准确判断预后和治疗方案选择提供参考，为基因治疗提供理论依据。

Megacystis Microcolon Intestinal Hypoperistalsis Syndrome (MMIHS) is a serious and rare disorder of enteric smooth muscle function with high mortality and unknown pathogenesis. It was found that the mutation sites p.R257H/C of ACTG2 were related to MMIHS. We recently found three novel mutated sites of ACTG2 in Chinese children with MMIHS (p.E196D，p.P113S and p.D245G). It is suggested that ACTG2 mutation may play a role in MMIHS by affecting actin polymerization, but it's still lack of evidence in vivo, and its mechanism remains unclear. Therefore, we will establish ACTG2-mutated mice model, and identify the specific role of ACTG2 mutations in the pathogenesis of MMIHS. Based studies for molecular networks, ultrastructure of cell, cellular communication, tissues and animal gastroenterology motility，we will determine the regulation of ACTG2 on contractile gene of smooth muscle cells. This study is of great significant for further elucidating the molecular mechanism of ACTG2 mutations, exploring the different clinical presentation and outcomes of MMIHS, to provide reference for accurate prognosis adn alternative therapy,and to provide theoretical basis for gene therapy.