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的营养物质，有助于维持水平衡，并保护我们的身体免受肠道内腔中存在的病原微生物的侵害，沿着大量有益细菌。为了使肠道执行其基本功能，它包含精致的专门细胞，包括上皮细胞，免疫细胞，神经细胞和肌肉细胞。肠上皮细胞彼此紧密连接，形成一个复杂的守门系统，允许营养物质和水的选择性运输，但阻止有害毒素或致病细菌。免疫细胞不断监测肠腔和肠壁，并在基本肠屏障被破坏的情况下做出反应。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组织来产生对适当消化功能至关重要的肠道运动。由于肠上皮细胞不断暴露于有害物质和病原微生物，它是相当脆弱的，往往受到损害。通常，这不会对生物体产生有害后果，因为肠上皮的所有细胞都由干细胞持续补充，这些干细胞致力于不断产生新鲜的上皮细胞。虽然肠上皮细胞的持续再生对于维持其良好的工作状态至关重要，但其他类型的细胞在保持健康方面发挥着重要作用。特别是，通常伴随和支持神经系统所有部分的神经细胞的神经胶质细胞也存在于肠上皮细胞附近，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神经胶质细胞，屏障就会破裂，动物会死于小肠的急性炎症。此外，一些研究表明，伴随常见肠道疾病（如克罗恩病或溃疡性结肠炎）的炎症也可能涉及神经胶质细胞与肠上皮细胞和免疫细胞的异常相互作用。这些观察结果支持了这样一种观点，即尽管它们具有特殊的功能，但组成肠壁的不同细胞类型（实际上是任何器官）需要协同工作以支持其生理作用。尽管肠神经胶质细胞在支持神经细胞和肠上皮的关键功能方面发挥重要作用，对它们在健康个体和疾病情况下的生物学知之甚少。在本提案中，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，我们将识别和鉴定在整个生命过程中产生新的神经胶质细胞的神经胶质干细胞的特性。我们还将确定调节肠神经胶质细胞行为的条件和信号。最后，我们计划研究位于细胞核内的分子，这些分子对于这些细胞在整个成年期保持其特性并继续产生新的胶质细胞至关重要。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良好平衡以及不同细胞类型之间的最佳串扰。这种平衡的破坏导致细胞的不受控制的生长（癌症）、肠壁的严重炎症（炎性肠病-IBD）或肠壁不能保护生物体的内部环境免受有毒物质或病原菌的侵害。了解局部神经胶质细胞如何促进肠道组织的完整性和正常功能，我们最终可以使用这些细胞作为改变常见衰弱性胃肠道疾病过程的手段。

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.