The MUC2 Mucus Gel as an Innate Immune Mechanisms that Inhibits Colitis

描述（由申请人提供）：覆盖我们粘膜表面的粘液是先天免疫系统的一个亲密部分，也是抵御微生物挑战的第一道防线。这在肠道的下部尤其突出，我们必须保护自己，同时我们生活在一种共生关系中，而不会引发明显的免疫反应。在一篇引领潮流的出版物（PNAS, 2008）中，我们可以证明结肠在MUC2粘蛋白周围有双层黏液层。它们的内部起着屏障的作用，不允许细菌渗透。由于粘液中没有MUC2或有缺陷，细菌到达上皮细胞，渗透到隐窝，并进入上皮细胞。在实验性结肠炎中，细菌可以穿透这种内部致密的黏液层，进一步证明这是理解肠道炎症和溃疡性结肠炎的关键。我们现在将研究黏液层是如何形成和构建的，使用生化方法，特别是质谱法，以及使用各种类型的基因敲除动物，这些动物被细菌或无菌定植。通过对活检中黏液层生长的研究，我们将描述引起溃疡性结肠炎的改变。重组黏液蛋白和药理学试剂将控制黏液的性质。预期结果是改善结肠保护的新方法，并通过这种新原理治疗溃疡性结肠炎。目的1。了解粘液及其主要成分MUC2粘蛋白如何保护结肠和小肠粘膜表面的功能。大肠中松散和坚固结肠粘液的分泌、形成和组成及其转化，包括对生物合成、0-糖基化、解包/分泌、体积膨胀、附着于上皮和免疫系统调节的理解。目标2。揭示MUC2黏液蛋白及其聚糖在结肠共生菌群选择中的作用以及细菌对内黏液层的影响。目标3。目的：探讨结肠内黏液层在溃疡性结肠炎（UC）中的作用。

DESCRIPTION (provided by applicant): The mucus covering our mucosal surfaces is an intimate part of the innate immune system and the first line of defense against microbial challenges. This is especially prominent in the lower parts of the intestine where we have to protect ourselves at the same time as we live in a symbiotic relation without trigger an overt immune response. In a trend-setting publication (PNAS, 2008) we could shown that colon has a double- layered mucus layer built around the MUC2 mucin. The inner of these act as a barrier and does not allow bacteria to penetrate. With an absence of MUC2 or defects in the mucus, bacteria reach the epithelial cells, penetrate into the crypts, and into the epithelial cells. In experimental colitis the bacteria can penetrate this inner dense mucus layer further proving that this is the key to an understanding of intestinal inflammation and ulcerative colitis. We will now study how the mucus layers are formed and built by the use of biochemical methods, especially mass spectrometry, and the use of various types of gene knock-out animals that are colonized with bacteria or germ-free. By studies on the growth of the mucus layers from biopsies we will characterize the alterations causing ulcerative colitis. The mucus properties will be manipulated by recombinant mucus proteins and pharmacological agents. Expected results are novel ways to improve the protection of colon and by this novel principle for treatment of the disease ulcerative colitis. Aim 1. To obtain a functional understanding of how the mucus and its main component, the MUC2 mucin, protect the mucosal surfaces of the colon and small intestine. Secretion, formation and components of the loose and firm colonic mucus in the large intestine and its transition This includes an understanding of biosynthesis, 0-glycosylation, unpacking/secretion, volume expansion, attachment to epithelia, and regulation by immune system. Aim 2. To unravel the role of the MUC2 mucin and its glycans in the selection of our colonic commensal bacterial flora and effects of bacteria on the inner mucus layer. Aim 3. To unravel the role of the inner colonic mucus layer in the disease Ulcerative Colitis (UC).