Paneth Cell Secreted Effectors in Mucosal Innate Immunity

黏膜组织的免疫系统必须有效地保护宿主免受病原体的入侵，而 促进与不同的定植微生物群的动态平衡相互作用。认清关键 实现这种微妙平衡的分子和机制仍然不完整，在关键的 知识。小肠的潘氏细胞向肠腔内分泌大量蛋白质和多肽。 调节宿主防御和维持动态平衡的相互关联的功能。引人入胜 包括我们在内的许多实验室公布的证据表明，潘氏细胞功能有缺陷 增加对慢性炎症性肠病(IBD)和肠道病原体的易感性。这 调查将集中在一种分泌的蛋白质上，我们的初步数据表明，这种蛋白质是 人类潘氏细胞的分泌蛋白，一种未被研究的肠道凝集素，名为intelectin。远程通信 直系同源基因广泛存在于动物界，从哺乳动物到无脊椎动物海鞘。最近出版的 有资料表明，伊特莱汀具有天然免疫的分子模式结合活性。 系统，因为它与各种微生物上发现的碳水化合物结合-通过与外环1，2相互作用 二醇-但由于空间位阻而不与宿主碳水化合物结合。我们的初步数据显示 肠溶素两种异构体(ITLN1和ITLN2)在小肠中的定性和定量异常 来自回肠克罗恩病(CD)患者的标本与对照进行比较。虽然在统计上有重要意义， 可能将这些变化与CD先天免疫受损联系在一起的机制尚不清楚，而且将是 调查过了。我们的假设是，基于已发表的和初步的数据，伊特莱汀是一种关键的调节剂 肠道中宿主与微生物的相互作用。目标1将确定ITLN1和ITLN1的相对表达水平 在小肠CD和对照标本中的ITLN_2，并对分离自 人的小肠。目的2研究肠凝素异构体的体外活性。目标3将 利用新生成的C57BL/6 Itln-/-建立intelectin表达的先天免疫学后果 老鼠。我们的目标是阐明对intelectin在粘膜保护中的作用的基本理解，以及 通过这样做，填补了我们对人类Paneth一种保守的、高度丰富的分泌蛋白的理解空白 细胞。这些研究的成功完成可能会对我们的机械论理解产生广泛的影响 小肠的先天免疫力。

The immune system of mucosal tissues must effectively protect the host from pathogen invasion, while facilitating homeostatic interactions with a diverse colonizing microbiota. A clear understanding of the key molecules and mechanisms that achieve this delicate balance remains incomplete, leaving a gap in critical knowledge. Paneth cells of the small intestine secrete large quantities of proteins and peptides into the lumen that mediate both interrelated functions of host defense and maintenance of homeostasis. Compelling published evidence from many laboratories, including ours, suggests that defective Paneth cell function increases susceptibility to chronic inflammatory bowel disease (IBD) and to enteric pathogens. This investigation will focus on a secreted protein that our preliminary data suggests is among the most abundant secretory proteins of human Paneth cells, an understudied intestinal lectin named intelectin. Intelectin orthologs widely span the animal Kingdom, from mammals to the invertebrate sea squirts. Recent published data demonstrate that intelectin has molecular pattern binding activity characteristic of the innate immune system, in that it binds to carbohydrates found on a variety microbes - through interaction with exocyclic 1, 2 diols - but does not bind to host carbohydrates because of steric hindrance. Our preliminary data identify qualitative and quantitative aberrations of the two isoforms of intelectin (ITLN1 and ITLN2) in small intestinal specimens from individuals with ileal Crohn's disease (CD) compared to controls. While statistically significant, the mechanisms that may tie these changes to impaired innate immunity in CD are unknown and will be investigated. Our hypothesis, based on published and preliminary data, is that intelectin is a critical mediator of host-microbe interaction in the intestine. Aim 1 will determine the relative expression levels of ITLN1 and ITLN2 in small intestinal CD and control specimens, and biochemically characterize intelectin isolated from human small intestine. Aim 2 will investigate the in vitro activity of intelectin isoforms in vitro. Aim 3 will establish innate immunological consequences of intelectin expression using newly generated C57BL/6 Itln-/- mice. Our goal is to elucidate a fundamental understanding on the role of intelectin in mucosal protection, and in so doing, fill a void in our understanding of a conserved, highly abundant secretory protein of human Paneth cells. Successful completion of these studies will likely have broad impact on our mechanistic understanding of innate immunity in the small intestine.