Contribution of desmosomal cadherins to tissue homeostatis of intestine and liver

细胞粘附、分化和增殖之间的动态关系对于组织稳态是至关重要的。桥粒是上皮组织中重要的粘附位点，通过锚定角蛋白中间丝细胞骨架介导机械稳定性。此外，已经表明桥粒组分有助于细胞分化并参与生长调节。为了在体内测试各种桥粒功能，我们已经产生了转基因小鼠，允许在肠细胞或肝细胞中暂时定义和细胞类型限制的桥粒特异性细胞-细胞粘附分子桥粒芯糖蛋白2的消耗。该项目的目标是了解桥粒芯糖蛋白2的缺失如何影响桥粒形成，更重要的是，受损的桥粒粘附如何影响具有低或高增殖活性的细胞类型的性质和动态行为（即，肠细胞和肝细胞）。为此，我们将比较临床特征，组织病理学，细胞粘附，细胞骨架组织，生长和基因转录缺乏桥粒芯糖蛋白2在肠道和肝脏的小鼠。此外，使用化学和遗传肿瘤模型，我们将确定改变的表型如何影响组织反应性，肿瘤生长，肿瘤分化和恶性转化。

The dynamic relationship between cell adhesion, differentiation and proliferation is of paramount importance for tissue homeostasis. Desmosomes are prominent adhesion sites in epithelial tissues mediating mechanical stability by anchoring the keratin intermediate filament cytoskeleton. In addition, it has been suggested that desmosomal components contribute to cell differentiation and participate in growth regulation. To test the various desmosomal functions in vivo, we have generated transgenic mice that allow temporally-defined and cell type-restricted depletion of the desmosomespecific cell-cell adhesion molecule desmoglein 2 either in enterocytes or hepatocytes. The goal of the project is to understand how the loss of desmoglein 2 affects desmosome formation and, more importantly, how compromised desmosomal adhesion influences the properties and dynamic behaviour of cell types with either low or high proliferative activity (i.e., enterocytes and hepatocytes, respectively) in health and disease. To this end, we will compare clinical features, histopathology, cell adhesion, cytoskeletal organisation, growth, and gene transcription in mice lacking desmoglein 2 in the intestine and liver. In addition, using chemical and genetic tumor models we will determine how the altered phenotypes affect tissue reactivity, tumor growth, tumor differentiation, and malignant transformation.