Homeostasis of Glial Cells in the Mammalian Gut

胃肠道是一个重要的器官，它将我们的饮食转化为有用的可消化营养物质，有助于维持水分平衡，并保护我们的身体免受肠道腔内存在的病原体以及大量有益细菌的影响。为了让肠道发挥其基本功能，它含有精致的专门化细胞，包括上皮细胞、免疫细胞、神经细胞和肌肉细胞。肠道上皮细胞彼此紧密相连，形成一个复杂的把关系统，允许营养物质和水的选择性运输，但防止有害毒素或病原体。免疫细胞持续监测肠腔和肠壁，并在基本肠道屏障被突破时做出反应。最后，肠壁内复杂的神经细胞网络负责通过激活肠壁的肌肉系统来产生肠道运动，这对正常的消化功能是必不可少的。由于肠道上皮不断暴露在有害物质和致病微生物中，它非常脆弱，经常受到破坏。正常情况下，这不会对生物体产生有害后果，因为肠上皮的所有细胞都不断地由干细胞补充，这些干细胞致力于产生不断新鲜的上皮细胞。虽然肠上皮的持续再生对于维持其良好的工作状态是必不可少的，但其他类型的细胞在保持其健康方面起着重要作用。特别是，在神经系统所有部分通常伴随和支持神经细胞的神经胶质细胞也在肠上皮细胞附近发现，并释放维持肠上皮屏障所必需的物质；如果在实验条件下消除这些肠胶质细胞，屏障就会被破坏，动物会死于小肠的急性炎症。此外，多项研究表明，常见肠道疾病伴随的炎症，如克罗恩病或溃疡性结肠炎，可能还涉及神经胶质细胞与肠道上皮细胞和免疫细胞的异常相互作用。这些观察结果支持这样一种观点，即尽管它们具有特殊的功能，但组成肠壁(甚至任何器官)的不同类型的细胞需要协同工作，才能支持其生理作用。尽管肠道神经胶质细胞在支持神经细胞和肠道上皮的关键功能方面发挥着重要作用，但人们对它们在健康个体和疾病情况下的生物学知之甚少。在这项提案中，我们将以我们自己最近的一些观察为基础，旨在填补这一知识空白。特别是，我们将鉴定和描述在一生中产生新的神经胶质细胞的胶质干细胞的特性。我们还将确定调节肠道神经胶质细胞行为的条件和信号。最后，我们计划描述位于细胞核内的分子，这些分子对这些细胞保持其特性并在成年后继续产生新的胶质细胞非常重要。正常的消化功能取决于不同肠道组织中旧细胞的丢失和新细胞的产生之间的微妙平衡，以及不同细胞类型之间的最佳串扰。这种平衡的破坏会导致细胞不受控制的生长(癌症)、肠壁的严重炎症(炎症性肠病-IBD)或肠壁无法保护生物体的内部环境免受有毒物质或致病细菌的伤害。了解局部胶质细胞如何促进肠道组织的完整性和正常功能，我们最终可以利用这些细胞作为一种手段来改变常见的衰弱胃肠道疾病的过程。

The gastrointestinal tract is a vital organ that converts our diet into useful digestible nutrients, contributes to the maintenance of water balance and protects our body from pathogenic microorganisms that are present within the lumen of the gut, along with large numbers of beneficial bacteria. In order for the gut to carry out its essential functions, it contains exquisitely specialised cells, including epithelial cells, immune cells, nerve cells and muscle cells. Intestinal epithelial cells are tightly connected to each other to form a sophisticated gatekeeping system that allows the selective transport of nutrients and water but keeps away harmful toxins or pathogenic bacteria. Immune cells constantly monitor the lumen and the wall of the gut and respond in case the essential intestinal barrier is breached. Finally, complex networks of nerve cells within the gut wall are responsible for generating intestinal movements that are essential for proper digestive function by activating the musculature of the gut wall. Since the intestinal epithelium is constantly exposed to harmful substances and pathogenic microorganisms, it is quite vulnerable and is often damaged. Normally this does not have detrimental consequences for an organism since all cells of the intestinal epithelium are continuously replenished by stem cells that are dedicated to producing constantly fresh epithelial cells. Although the continuous regeneration of the intestinal epithelium is essential for maintaining it in good working order, other cell types play a major role in keeping them healthy. In particular, glial cells, which normally accompany and support nerve cells in all parts of the nervous system, are also found in the vicinity of intestinal epithelial cells and release substances that are essential for maintaining the intestinal epithelial barrier; if these enteric glial cells are eliminated in experimental conditions, the barrier breaks down and animals die from acute inflammation of the small intestine. In addition, several studies have suggested that the inflammation that accompanies common gut diseases, such as Crohn's disease or ulcerative colitis, may also involve the abnormal interaction of glial cells with intestinal epithelial cells and immune cells. These observations support the idea that despite their specialised functions, the different cell types that make up the gut wall (and indeed any organ) need to work in concert in order to support its physiological roles.Despite the important roles of the intestinal glial cells in supporting the critical functions of the nerve cells and the epithelium of the gut, very little is known about their biology in healthy individuals and in disease situations. In this proposal we will aim at filling this knowledge gap by building on some of our own recent observations. In particular, we will identify and characterise the properties of the gliogenic stem cells which generate new glial cells throughout life. We will also identify conditions and signals that modulate the behaviour of intestinal glial cells. Finally, we plan to characterise molecules which are located within the nucleus and are important for these cells to maintain their properties and continue to generate new glial cells throughout adult life.Normal digestive function depends on the fine balance between the loss of old and the production of new cells in the different gut tissues and the optimal cross talk between the different cell types. Breakdown of such an equilibrium results in uncontrolled growth of cells (cancer), severe inflammation of the gut wall (inflammatory bowel disease-IBD) or inability of the gut wall to protect the internal environment of an organisms from toxic substances or pathogenic bacteria. Understanding how local glial cells contribute to the integrity and normal function of gut tissues, we can ultimately use these cells as a means to alter the course of common debilitating gastrointestinal disorders.