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

描述(申请人提供)：覆盖在我们粘膜表面的粘液是天然免疫系统的亲密部分，是抵御微生物挑战的第一道防线。这在肠道的下部尤为明显，我们必须在保护自己的同时，在不引发明显免疫反应的情况下共生。在一份引领潮流的出版物(PNAS，2008)中，我们可以证明，结肠有一个围绕MUC2粘蛋白构建的双层粘液层。这些细菌的内部起到了屏障的作用，不允许细菌渗透。如果没有MUC2或粘液中有缺陷，细菌就会到达上皮细胞，穿透到隐窝，进入上皮细胞。在实验性结肠炎中，细菌可以穿透内部致密的粘液层，进一步证明这是了解肠道炎症和溃疡性结肠炎的关键。我们现在将通过使用生化方法，特别是质谱学，以及使用各种类型的有细菌或无菌的基因敲除动物来研究粘液层是如何形成和建立的。通过对活检粘液层生长的研究，我们将确定引起溃疡性结肠炎的变化的特征。粘液特性将由重组粘液蛋白和药理制剂来操纵。预期的结果是改善对结肠的保护的新方法，并通过这一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的粘膜表面。大肠中疏松而坚硬的结肠粘液的分泌、形成和成分及其转化。这包括对生物合成、0-糖基化、解包/分泌、体积膨胀、附着于上皮细胞以及免疫系统的调节的理解。目的2.揭示MUC2粘蛋白及其多糖在我们的结肠共生菌群选择中的作用以及细菌对内粘液层的影响。目的3.揭示结肠内粘液层在溃疡性结肠炎(UC)发病中的作用。

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).