Nod2-mediated regulation of intestinal homeostasis

Nod2介导的肠道稳态调节

• 批准号: 7769747
• 负责人: KOICHI S KOBAYASHI
• 金额: $ 0.17万
• 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/7769747
• 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（由申请人提供）：健康肠道的特征是持续的、控制良好的炎症。这是由肠道上皮正常菌群的相互作用引起的，正常菌群通常处于稳态状态。一旦这种平衡被打破，免疫系统就会随着炎症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。本项目的总体目标是确定肠道先天免疫系统与肠道内共生或致病菌群维持稳态的分子机制。最近发现的一个属于Nod或NBD-LRR蛋白家族的蛋白质为我们对细菌识别的理解提供了新的视角。Nod蛋白Nod2检测细菌细胞壁的部分，其突变通过未知机制与克罗恩病相关。Nod2突变等位基因的拷贝使克罗恩病的风险增加约2-4倍，而Nod2突变的纯合或复合杂合使风险增加约40倍，表明Nod2突变以隐性方式作用于克罗恩病。我们最近的研究表明，Nod2通过识别细菌肽聚糖片段MDP （muramyl dipetide）激活先天和适应性免疫反应，并通过调节肠道抗微生物肽亚群的表达来保护肠道免受细菌感染。因此，我们假设Nod2通过检测肠道中的细菌或细菌成分和优化抗菌肽的产生来控制共生菌和致病菌，从而维持肠道内的稳态。这些假设将通过针对以下具体目标的研究进行评估。目的1提出定义nod2介导的信号通路，导致肠道中抗微生物肽的表达。目的2通过小鼠结肠炎模型研究Nod2对肠道稳态的影响。目的3提出确定参与nod2依赖性肠道病理的细胞类型。这些研究为肠道内稳态机制和Nod2的生理功能提供了新的认识，对炎性肠病的发病机制具有重要意义。