Nod2: A Susceptibility Gene for Crohn's Disease

Nod2：克罗恩病的易感基因

基本信息

批准号：
7502762
负责人：
Gabriel Nunez
金额：
$ 30.79万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-04-08 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7502762
关键词：
Acetylmuramyl-Alanyl-Isoglutamine Address Adjuvant Affect Animals Antibody Formation Bacteria Binding Biochemical Caspase-1 Caucasians Caucasoid Race Cell physiology Cells Chimera organism Chromosomes, Human, Pair 16 Chronic Class Crohn&apos s disease Defensins Development Disease Enterobacteriaceae Genetic Genetic Variation Goals Host Defense Ileal Diseases Ileitis Immunity Individual Indomethacin Inflammation Inflammatory Response Inflammatory disease of the intestine Intestines Intravenous Knockout Mice Lead Link Listeria MAP Kinase Gene MAPK Signaling Pathway Pathway Maps Modeling Mus Mutation Natural Immunity Oral Oral Administration Paneth Cells Pathogenesis Pattern recognition receptor Peptides Peptidoglycan Peritoneal Phosphotransferases Play Population Predisposition Proteins Regulation Risk Role Small Intestines Susceptibility Gene Thinking Tissues United States antimicrobial base cryptdin gain of function mutation human study in vivo macrophage mutant pathogen pathogenic bacteria protein function response

项目摘要

DESCRIPTION (provided by applicant): Crohn's disease (CD) is a chronic and debilitating disease affecting more than 500,000 individuals in the United States and millions worldwide. Both environmental (particularly enteric bacteria) and genetic factors are known to play a critical role in the development of CD. Recent studies have revealed that genetic variation in NOD2 is associated with susceptibility to CD and specifically with ileal disease. NOD2 is an intracellular pattern recognition receptor that is activated by muramyl dipeptide (MDP), a conserved motif in peptidoglycan (PGN) that is known to elicit potent adjuvant activity for antibody production in vivo. Upon activation, NOD2 binds the RICK/RIP2 kinase and activates NF-:B and MAPK signaling pathways leading to the induction of multiple host defense molecules. Homozygosity or compound heterozygocity for NOD2 mutations increases the risk 20-40-fold while heterozygosity lead to minimal increase in risk, indicating that loss of NOD2 function is important for disease development. Consistent with the genetic observations, all three CD-associated NOD2 mutations result in proteins that are deficient in inducing NF-?B activation in response to bacterial components including PGN and MDP. The ability of NOD2 to activate NF-?B in response to bacteria suggests that defective sensing of intestinal bacteria somehow promotes susceptibility to disease. However, many questions remain including how NOD2 mutations contribute to CD and why NOD2 mutations are associated with ileal disease. Furthermore, the role of NOD2 in CD pathogenesis is unclear because animal studies have suggested that the CD- associated L1007insC NOD2 mutation functions as a gain-of-function mutation. Notably, Nod2-null mice are highly susceptible to oral inoculation but not intravenous or intra- peritoneal administration of Listeria, indicating that Nod2 plays a role in intestinal immunity to control pathogenic bacteria. Furthermore, NOD2 is expressed in Paneth cells located at the base of the crypts of Liberk|hn in the small intestine providing a possible link between NOD2 and ileal disease. Consistent with the latter, recent results have implicated Nod2 in the regulation of 1-defensins, a class of anti-microbial peptides produced by Paneth cells. The goal of this proposal is to address the role of Nod2 in intestinal immunity and in the pathogenesis of CD using genetically manipulated mice that are deficient in Nod2 or expressed the common CD-associated L1007insC Nod2 mutation.Both environmental (particularly enteric bacteria) and genetic factors are known to play a critical role in the development of Crohn's disease (CD). Recent studies have revealed that genetic variation in NOD2, an intracytoplasmic pattern recognition receptor, is associated with susceptibility to CD, but the mechanism involved is poorly understood. This proposal will address the role of Nod2 in intestinal immunity and in the pathogenesis of CD using genetically manipulated mice that are deficient in Nod2 or expressed the common CD-associated L1007insC Nod2 mutation.

描述（由申请人提供）：克罗恩病 (CD) 是一种慢性且使人衰弱的疾病，影响着美国超过 500,000 人以及全世界数百万人。已知环境因素（特别是肠道细菌）和遗传因素在克罗恩病的发生中发挥着关键作用。最近的研究表明，NOD2 的遗传变异与 CD 易感性有关，特别是与回肠疾病有关。 NOD2 是一种细胞内模式识别受体，由胞壁酰二肽 (MDP) 激活，胞壁酰二肽 (MDP) 是肽聚糖 (PGN) 中的保守基序，已知可在体内激发抗体产生的有效佐剂活性。激活后，NOD2 结合 RICK/RIP2 激酶并激活 NF-:B 和 MAPK 信号通路，从而诱导多种宿主防御分子。 NOD2突变的纯合性或复合杂合性使风险增加20-40倍，而杂合性导致风险增加最小，表明NOD2功能的丧失对于疾病的发展很重要。与遗传观察一致，所有三种 CD 相关的 NOD2 突变都会导致蛋白质缺乏诱导 NF-κB 激活以响应包括 PGN 和 MDP 在内的细菌成分。 NOD2 响应细菌而激活 NF-κB 的能力表明，肠道细菌的感知缺陷在某种程度上会促进疾病的易感性。然而，仍然存在许多问题，包括 NOD2 突变如何导致 CD 以及为什么 NOD2 突变与回肠疾病相关。此外，NOD2 在 CD 发病机制中的作用尚不清楚，因为动物研究表明 CD 相关的 L1007insC NOD2 突变起到功能获得性突变的作用。值得注意的是，Nod2缺失小鼠对口服接种李斯特菌高度敏感，但对静脉内或腹膜内施用李斯特菌不敏感，这表明Nod2在控制病原菌的肠道免疫中发挥作用。此外，NOD2 在位于小肠 Liberk|hn 隐窝底部的潘氏细胞中表达，这提供了 NOD2 与回肠疾病之间可能的联系。与后者一致的是，最近的结果表明 Nod2 参与了 1-防御素（潘氏细胞产生的一类抗菌肽）的调节。该提案的目标是使用缺乏 Nod2 或表达常见 CD 相关 L1007insC Nod2 突变的基因操作小鼠来解决 Nod2 在肠道免疫和 CD 发病机制中的作用。环境（特别是肠道细菌）和遗传已知因素在克罗恩病 (CD) 的发展中发挥着关键作用。最近的研究表明，NOD2（一种胞质内模式识别受体）的遗传变异与 CD 易感性相关，但所涉及的机制尚不清楚。该提案将使用缺乏 Nod2 或表达常见 CD 相关 L1007insC Nod2 突变的基因操作小鼠来探讨 Nod2 在肠道免疫和 CD 发病机制中的作用。