Nod2-mediated regulation of intestinal homeostasis

Nod2介导的肠道稳态调节

• 批准号: 7617110
• 负责人: KOICHI S KOBAYASHI
• 金额: $ 27.67万
• 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/7617110
• 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）：健康肠道的特点是持续、良好控制的炎症。这是由通常处于稳态状态的肠上皮正常菌群相互作用引起的。一旦这种平衡被打破，免疫系统就会长期激活，导致炎症细胞因子的过度产生，从而导致炎症性肠病的发生。该项目的总体目标是确定肠道先天免疫系统与肠道共生菌或致病菌菌群维持稳态的分子机制。最近对 Nod 或 NBD-LRR 蛋白家族的发现为我们对细菌识别的理解提供了新的线索。 Nod2 是一种 Nod 蛋白，可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 突变等位基因的副本会使克罗恩病的风险增加约 2-4 倍，而 Nod2 突变的纯合性或复合杂合性会使风险增加约 40 倍，表明 Nod2 突变以隐性方式作用于克罗恩病。我们最近发现，Nod2 通过识别 MDP（细菌肽聚糖的一部分）来激活先天性和适应性免疫反应，并通过调节肠道抗菌肽亚组的表达来保护肠道免受细菌感染。因此，我们假设Nod2通过检测细菌或细菌成分以及优化肠道内抗菌肽的产生来控制共生菌和病原菌，从而维持肠道稳态。这些假设将通过针对以下具体目标的研究进行评估。目标 1 提议定义 Nod2 介导的信号通路，导致抗菌肽在肠道中表达。目标 2 提议通过使用小鼠结肠炎模型来描述 Nod2 对肠道稳态的影响。目标 3 提议确定参与 Nod2 依赖性肠道病理学的细胞类型。这些研究应该为肠道稳态机制和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。