The role of the transfer RNA repertoire in generating secretory phenotypes during epithelial homeostasis

像肠道这样的器官需要不断地更新它们的细胞以保持完整性。为了做到这一点，肠道中有一小群干细胞，它们不断生长和分裂，提供新细胞的供应，以支持肠道功能。这些干细胞位于肠道隐窝的一个特殊的生态位中，它们产生的细胞供应从隐窝转移到肠膜的其他部分。离开隐窝后，肠道细胞停止分裂，开始执行其他重要功能，如分泌帮助消化的分泌物。所有细胞都制造蛋白质，它们制造的蛋白质目录根据它们的功能而变化。因此，快速增殖的肠道干细胞群必须制造蛋白质来支持细胞生长和分裂。然而，当肠道细胞离开隐窝并停止生长时，它们就停止制造用于细胞生长的蛋白质，转而大规模生产分泌物。细胞的蛋白质合成机制必须适应它产生的蛋白质菜单的这种重大变化。该项目将研究当细胞离开肠隐窝中的干细胞生态位，停止分裂并开始大量分泌蛋白质时，蛋白质合成机制发生的变化。然后，我们将制造具有改变的蛋白质合成机制的转基因小鼠，以确定这如何影响肠道的分泌功能和完整性。这些转基因老鼠和我们从它们身上获得的信息将使我们能够确定像肠道这样的复杂组织是如何构建自身的，以及它是如何执行营养物质吸附和维持肠道微生物群等功能的。

Organs such as the intestine need to constantly renew their cells in order to maintain integrity. To do this, the intestine has a small population of stem cells which keep growing and dividing to provide a supply of new cells to support gut function. These stem cells are situated in a special niche in the crypts of the gut, and the supply of cells that they produce move out of the crypt and into other parts of the intestinal membrane. Upon leaving the crypt, gut cells stop dividing and start to perform other important functions, such as the production of secretions that assist digestion. All cells make proteins, and the catalogue of proteins that they make varies according to their function. Thus the population of gut stem cells that are rapidly proliferating must make proteins to support cell growth and division. However, when gut cells leave the crypt and stop growing, they cease to make proteins for cell growth and turn their hand to large-scale production of secretions. The cell's protein synthesis machinery must adapt to this major change in the menu of proteins it produces. This project will investigate the alterations to the protein synthesis machinery that occur as cells leave the stem cell niche in the intestinal crypt, stop dividing and start to make secreted proteins in large quantities. We will then make genetically-modified mice with altered protein synthesis machinery to determine how this influences the secretory function and integrity of the intestine. These genetically modified mice and the information that we gain from them will enable us to determine how a complex tissue like the gut is able to structure itself, and how it perform functions such as nutrient adsorption and the maintenance of the gut microbiota.