Nod2-mediated regulation of intestinal homeostasis

描述（由申请人提供）：健康肠道的特征是持续、控制良好的炎症。这是由肠上皮正常细菌植物群的相互作用引起的，通常处于稳态。一旦这种平衡被打破，免疫系统就会被长期激活，产生过多的炎性细胞因子，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中的细菌或病原性植物群保持稳态的分子机制。最近的发现属于Nod或NBD-LRR蛋白的蛋白质家族为我们理解细菌识别提供了新的思路。一种Nod蛋白，Nod 2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。Nod 2的突变等位基因的拷贝使克罗恩病的风险增加约2-4倍，而Nod 2突变的纯合性或复合杂合性使风险增加约40倍，表明Nod 2中的突变以隐性方式对克罗恩病起作用。我们最近发现，Nod 2通过识别MDP（胞壁酰二肽）（细菌肽聚糖的一部分）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Nod 2通过检测细菌或细菌成分和肠道中抗菌肽的最佳产生来控制肠道和致病菌，从而维持肠道内稳态。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提出确定Nod 2介导的导致肠道中抗菌肽表达的信号通路。目的2提出通过小鼠结肠炎模型来阐明Nod 2对肠道稳态的影响。目的3提出确定参与Nod 2依赖性肠道病理学的细胞类型。这些研究将为阐明Nod 2在肠道内稳态调节中的作用机制和生理功能提供新的思路，对炎症性肠病的发病机制具有重要意义。

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.