Regulation of epithelial apical membrane differentiation and function

上皮细胞是连续的细胞层，划分我们的组织和器官。单个上皮细胞通过介导粘附的分子复合物相互作用，但也作为传感器将邻近细胞存在或不存在的信息传递到细胞内部。上皮的完整性对于我们器官的正常发育和功能，以及保护我们免受环境的影响是很重要的。例如，皮肤等上皮层或肠道内壁的破裂可导致严重感染，并可能由于慢性炎症或病毒和细菌的急性感染而发生。同样，癌细胞的一个特征是，它们失去了感知邻近细胞存在的能力，也失去了感知邻近细胞堆积程度的能力，因此它们继续在邻近细胞的上面增殖和迁移。上皮细胞是极化的，这意味着它们有两个具有不同组成和功能的细胞表面结构域。在我们的器官中，面向外部世界或内部腔的细胞表面称为顶细胞表面。这个顶域通常形成一个高度特化的结构，调节器官的特定功能，如肠道的消化和营养吸收，或支持我们眼睛中感光细胞的功能。在这里，我们建议研究驱动肠和视网膜上皮细胞形成这种特化顶端膜的分子机制。这一途径是基于我们最近发现的信号蛋白，我们有证据表明它们形成了一种机制，可以抑制与肿瘤发生和癌症有关的蛋白质的功能，通过刺激细胞分化和形成紧密排列的细胞片。了解上皮细胞如何分化介导器官特异性功能，以及这些途径如何抑制可能导致癌症的机制，对于了解组织在疾病中的行为是很重要的。上皮功能障碍与许多疾病有关，如癌症、肠道慢性炎症以及导致失明的遗传性和年龄相关疾病。预期的结果将帮助我们思考如何治疗导致上皮变性和癌症的疾病的新方法。

Epithelia are continuous layers of cells that delineate our tissues and organs. Individual epithelial cells interact with each other via molecular complexes that mediate adhesion but also function as sensors that transmit information about the presence or absence of neighbouring cells to the cell interior. Integrity of epithelia is important for our organs to develop and function normally, and to protect us from our environment. For example, breaches in epithelial layers such as the skin or in the lining of the intestine can lead to serious infections and can occur due to chronic inflammations or acute infections by viruses and bacteria. Similarly, a characteristic of cancer cells is that they have lost the capability to sense the presence of neighbouring cells or how tightly they are packed, and hence continue to proliferate and migrate on top of their neighbours. Epithelia are polarised, which means they have two cell surface domains that have different compositions and functions. The cell surface that faces the outside world or the internal lumen in our organs is called the apical cell surface. This apical domain often forms a highly specialised structure that mediates organ specific functions, such as digestion and nutrient absorption in the intestine or supportive functions for the cells that sense light in our eyes. Here, we propose to investigate a molecular mechanism that drives the formation of such specialised apical membranes in intestinal and retinal epithelial cells. This pathway is based on signalling proteins that we have recently identified and for which we have evidence that they form a mechanism that may also inhibit the function of proteins that have been linked to tumorigenesis and cancer by stimulating cells to differentiate and form tightly packed cellular sheets. Knowledge of how epithelial cells differentiate to mediate organ specific functions and how such pathways inhibit mechanisms that can lead to cancer is important to understand how tissues behave in disease. Epithelial dysfunction has been linked to many diseases such as cancer, chronic inflammations in the intestine, and inherited and age-related diseases that lead to blindness. The expected results will help us to think of new ways how we can treat such diseases that lead to epithelial degeneration and cancer.