Nod2: A Susceptibility Gene for Crohn's Disease

Nod2：克罗恩病的易感基因

• 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
• 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' 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

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，影响了美国和全球500,000多人。已知环境（尤其是肠细菌）和遗传因素在CD的发展中起着至关重要的作用。最近的研究表明，NOD2的遗传变异与对CD的敏感性，特别是与回肠疾病有关。 NOD2是一种细胞内模式识别受体，被穆拉米基二肽（MDP）激活，穆拉米基二肽（MDP）是一种肽聚糖（PGN）中的保守基序，已知会引起体内抗体生产的有效辅助活性。激活后，NOD2结合RICK/RIP2激酶并激活NF-：B和MAPK信号传导途径，导致多个宿主防御分子的诱导。 NOD2突变的纯合性或复合杂合性增加了风险20-40倍，而杂合性的风险最小，这表明NOD2功能的丧失对疾病的发展很重要。与遗传观察一致，所有三个与CD相关的NOD2突变都导致蛋白质不足，这些蛋白质因响应包括PGN和MDP在内的细菌成分而诱导NF-？B激活。 NOD2激活NF-？B以响应细菌的能力表明，肠道细菌的有缺陷以某种方式促进了对疾病的易感性。但是，仍然存在许多问题，包括NOD2突变如何促进CD以及为什么NOD2突变与回肠疾病有关。此外，NOD2在CD发病机理中的作用尚不清楚，因为动物研究表明CD相关的L1007INSC NOD2突变是功能奖励突变。值得注意的是，NOD2-NULL小鼠高度易于口服接种，而不是静脉内或腹膜内给药李斯特菌，这表明NOD2在控制致病细菌的肠道中起作用。此外，NOD2在小肠中自由行| Hn隐窝底部的Paneth细胞中表达，从而提供了NOD2和回肠疾病之间的可能联系。与后者一致，最近的结果暗示了NOD2在调节1-防御素的调节中，这是Paneth细胞产生的一类抗微生物肽。该提案的目的是解决NOD2在肠道免疫中的作用和CD的发作，使用遗传操纵的小鼠在NOD2中缺乏或表达了常见的CD相关L1007INSC NOD2突变。已知在CROHS的疾病中起着至关重要的作用。最近的研究表明，NOD2的遗传变异是一种胞质内模式识别受体，与CD的敏感性有关，但所涉及的机制知之甚少。该建议将使用遗传操纵的小鼠在NOD2缺乏或表达与常见的CD相关的L1007INSC NOD2突变中，解决NOD2在肠道免疫和CD发病机理中的作用。