Nod2-mediated regulation of intestinal homeostasis

Nod2介导的肠道稳态调节

• 批准号: 7417807
• 负责人: KOICHI S KOBAYASHI
• 金额: $ 27.72万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-05 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7417807
• 关键词: Accounting; Acetylmuramyl-Alanyl-Isoglutamine; Address; Adoptive Transfer; Alleles; Anti-Bacterial Agents; Bacteria; Bacterial Infections; Bone Marrow Cells; Cell Wall; Colitis; Crohn' s disease; Defensins; Dendritic Cells; Detection; Development; Doctor of Medicine; Doctor of Philosophy; Enteral; Epithelium; Equilibrium; Functional disorder; Gene Mutation; Generations; Genes; Goals; Helicobacter hepaticus; Homeostasis; Human; Immune response; Immune system; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Intestines; Laboratories; Light; Maintenance; Mediating; Modeling; Molecular; Mus; Mutate; Mutation; Paneth Cells; Pathogenesis; Pathology; Patients; Peptides; Peptidoglycan; Phosphotransferases; Production; Protein Family; Proteins; Reagent; Receptor Signaling; Regulation; Research; Research Personnel; Risk; Role; Signal Pathway; Signal Transduction; Subgroup; Susceptibility Gene; Technology; Testing; Toll-like receptors; antimicrobial; cell type; commensal microbes; cryptdin; cytokine; insight; interest; intestinal epithelium; leucine-rich repeat protein; macrophage; novel; pathogenic bacteria; programs

DESCRIPTION (provided by applicant): The healthy intestinal tract is characterized by continuous, well-controlled inflammation. This is caused by an interaction of the enteric epithelium normal bacterial flora that are usually in a state of homeostasis. Once this balance is broken, the immune system becomes chronically activated with overproduction of inflammatory cytokines, leading to the development of inflammatory bowel disease. The overall goal of this project is to define the molecular mechanisms by which the intestinal innate immune system maintains homeostasis with commensal or pathogenic bacterial flora in the gut. Recent findings of a family of proteins belonging to Nod or NBD-LRR proteins shed a new light on our understanding of bacterial recognition. One Nod protein, Nod2 detects moieties of the bacterial cell wall and its mutation is associated with Crohn's disease via unknown mechanisms. A copy of the mutated alleles of Nod2 increases the risk for Crohn's disease by ~2-4 fold whereas homozygosity or compound heterozygosity of Nod2 mutations increases the risk ~40 fold, suggesting mutations in Nod2 act in a recessive fashion for Crohn's disease. We have recently shown that Nod2 activates innate and adaptive immune responses through recognition of MDP (muramyl dipetide), a moiety of bacterial peptidoglycan, and protects the intestine from bacterial infection by regulating expression of a subgroup of intestinal anti-microbial peptides. Therefore, we hypothesize that Nod2 maintains intestinal homeostasis by controlling commensal and pathogenic bacteria via detection of bacteria or bacterial components and optimum production of anti-bacterial peptides in the intestine. These hypotheses will be evaluated by studies addressing the following specific aims. Aim 1 proposes to define the Nod2-mediated signaling pathways leading to the expression of anti-microbial peptides in the intestine. Aim 2 proposes to delineate the effect of Nod2 on intestinal homeostasis by using mouse colitis models. Aim 3 proposes to determine the cell types involved in Nod2-dependent intestinal pathology. These studies should provide novel insights into the mechanism of intestinal homeostasis and the physiological functions of Nod2, which is of great significance to the pathogenesis of inflammatory bowel disease.

描述(申请人提供)：健康的肠道以持续的、控制良好的炎症为特征。这是由肠道上皮正常的细菌菌群相互作用引起的，这些菌群通常处于动态平衡状态。一旦这种平衡被打破，免疫系统就会随着炎性细胞因子的过度产生而长期激活，从而导致炎症性肠病的发展。这个项目的总体目标是确定肠道天然免疫系统与肠道内共生或致病细菌群保持动态平衡的分子机制。最近一个属于NOD或NBD-LRR蛋白家族的发现为我们理解细菌识别提供了新的线索。NOD蛋白NOD2检测到细菌细胞壁的部分，它的突变与克罗恩病有关，机制不明。NOD2突变等位基因的副本使克罗恩病的风险增加~2-4倍，而NOD2突变的纯合子或复合杂合子使风险增加约40倍，这表明NOD2突变对克罗恩病起隐性作用。我们最近发现，NOD2通过识别细菌多肽的一部分MDP(胞壁酰二肽)来激活先天和获得性免疫反应，并通过调节肠道抗菌肽的亚群的表达来保护肠道免受细菌感染。因此，我们推测，NOD2通过检测细菌或细菌成分并优化肠道抗菌肽的产生来控制共生细菌和病原菌，从而维持肠道内的动态平衡。这些假设将通过涉及以下具体目标的研究进行评估。目的1确定NOD2介导的信号通路导致肠道中抗菌肽的表达。目的2利用小鼠结肠炎模型研究NOD2对肠道内环境平衡的影响。目的3建议确定NOD2依赖的肠道病理所涉及的细胞类型。这些研究将对肠道内稳态的机制和NOD2的生理功能提供新的见解，这对炎症性肠病的发病机制具有重要意义。