肠道稳态维持的调控机理

The gut homeostasis is maintained by intestinal stem cell (ISC) through its self-renewal, proliferation and differentiation. Deregulation of gut homeostasis is associated with related human digestive diseases and cancers. Intensive studies have demonstrated that several signaling pathways, including Wnt, BMP, and Notch, cooperate to regulate the maintenance of intestinal homeostasis. However, it is unknown how these signaling pathways integrate at the transcription level to regulate ISC maintenance or differentiation. This application focuses on the regulation of intestinal homeostasis and stem cell activities by a Znhit1. We have generated a Znhit1 mutant Drosophila and mouse lines. Our preliminary studies showed that loss of Znhit1 lead to intestinal epithelium leads to ISC ablation and cell differentiation defects. In this proposal, we will use both Drosophila and mouse models to further define the regulatory mechanisms by which Znhit1 regulates intestinal homeostasis and stem cell activities. First, we will examine the roles of Znhit1 in ISC using Drosophila midgut model. Second, we will use mouse model to determine the roles of Znhit1 in regeneration of intestine after injury and in regulating ISC maintenance and differentiation. Finally, we will examine the functions of Znhit1 in development of colon cancers in mouse. The outcomes of this will shed light on human diseases associated with deregulation of ISC activities and gut homeostasis.

肠道稳态的维持是通过肠干细胞自我更新、增殖和分化来实现的，其稳态丧失与多种肠道疾病和癌症相关。大量的实验证明Wnt, BMP和Notch 等信号通路协同调控肠道稳态的维持。但这些信号通路如何在转录层面上整合从而调控肠道稳态和肠干细胞活性并不清楚。该项目致力于研究肠道稳态和肠干细胞活性如何受锌指核蛋白Znhit1的调控。我们已经获得果蝇和小鼠的Znhit1突变品系，初步实验表明：Znhit1 缺失导致肠干细胞功能损伤和细胞分化缺陷。本项目将用果蝇和小鼠模型进一步阐明Znhit1调控肠道稳态和肠干细胞活性的机制。首先，在果蝇中肠系统中研究Znhit1调控肠道稳态的机制；其次，在小鼠中阐明Znhit1对小肠损伤后再生的作用，以及肠干细胞自我更新和分化的调控机制;最后，在小鼠中阐明Znhit1对结肠癌发生发展的作用及分子机制。该项目的实施将有助于我们加深对肠道稳态丧失导致的相关人类疾病的了解。

组织稳态丧失通常会导致组织再生障碍与肿瘤等多种疾病的发生。成体干细胞的维持、增殖与分化受到表观遗传、信号转导与蛋白质稳态等多层次的机制调控，对于器官再生和维持组织稳态至关重要。我们围绕“肠道稳态维持的调控机制”这一核心科学问题，针对肠上皮干细胞命运决定和组织稳态维持中的调控机制，从表观遗传、蛋白质质量控制与信号转导三个层面开展了系统性的研究。我们的工作阐明了表观遗传因子Znhit1通过组蛋白变体H2A.Z调控Lgr5+肠上皮干细胞维持的作用机理，揭示了内质网复合体核心蛋白Emc3调控肠上皮干细胞分化和肠炎发生的功能与分子机制。与此同时，我们研究了硫酸肝素调控重要的消化器官胃脏发育的功能。进一步的研究工作解析了Znhit1介导的染色质重塑整合关键细胞信号、协同组织特异性转录因子调控细胞命运决定和组织器官发育的重要机制。利用果蝇发育模型，探索了Znhit1调控H2Av整合和细胞凋亡的功能。通过建立类器官模型，探讨了新冠病毒感染和损害内胚层重要消化道器官（以肝脏为例）的机制。取得的一系列原创研究成果已发表在 Nature Communications，Developmental Cell，Protein & Cell，Leukemia，Sci China Life Sci，Mucosal Immunology，PLoS Genetics，Journal of Cell Science，Journal of Biological Chemistry 等杂志上。