内质网膜蛋白复合体调控肠道干细胞增殖和肠道稳态的分子机制研究

成体干细胞的维持、增殖和分化是实现组织稳态的关键，该过程失调会导致肿瘤和早衰等一系列重大疾病的发生，因此解开干细胞增殖与分化的调控机制是阐明组织稳态的关键。本项目利用成体果蝇中肠作为模型，研究内质网膜蛋白复合体（EMC）调控肠道干细胞的增殖与分化和肠道稳态的分子机制。我们已完成了果蝇全基因组RNAi体内筛选，获得了包括EMC在内的一系列调控肠道干细胞维持、增殖与分化的全新内源因子。我们发现EMC缺失后肠道干细胞的增殖和分化出现严重缺陷，肠道稳态丧失，导致肠道肿瘤的产生；通过IP-MS技术，我们已经鉴定了EMC复合体组份EMC1的互作蛋白。我们将通过遗传、发育、细胞和生化等多种技术手段，探讨EMC维持肠道稳态的作用机制，阐明其调控肠道干细胞增殖与分化的分子机理。由于果蝇和脊椎动物的消化系统在发育等过程中具有很大的相似性，本项目的实施将为研究干细胞的增殖与分化、稳态维持和癌症发生奠定理论基础。

The maintenance and differentiation of adult stem cells are responsible for residential tissue homeostasis, dis-regulation of stem cell maintenance and differentiation will lead to severe diseases like cancer and aging, studying the underlying mechanisms regulating stem cell proliferation and differentiation is critical for the understanding of tissue homeostasis control. Using adult Drosophila intestine as a model, we will investigate the molecular mechanism of Endoplasmic Reticulum (ER) Membrane Protein Complex (EMC) in controlling stem cell proliferation, differentiation, and midgut homeostasis. We had completed a genome-wide RNAi screen to identify intrinsic factors regulating intestinal stem cell maintenance, proliferation, and differentiation. A cohort of novel intrinsic factors involved in the regulation of stem cell maintenance, proliferation, and differentiation was identified, including the EMC complex. Our results showed that the EMC complex is critical for intestinal stem cell proliferation and differentiation. Intestinal stem cell proliferation and differentiation are aberrant in the absence of different EMC subunits, leading to midgut homeostasis loss and tumorigenesis. Importantly, we had identified the proteins associating with EMC1 through immunoprecipitation-mass spectrometry (IP-MS) technology. In this study, we will utilize methods in genetics, developmental biology, cell biology, and biochemistry to explore the biological roles EMC played in controlling intestinal stem cell proliferation, differentiation, and midgut homeostasis control, thereby elucidating its molecular mechanism(s) in midgut homeostasis control. As Drosophila midgut shares extensive similarities with its mammalian counterpart genetically and functionally, this study will elucidate the underlying mechanisms in homeostasis control by EMC to help the understanding of stem cell proliferation/differentiation, homeostasis control, and tumorigenesis, having potential clinical importance.