Defining the role of Nod2 and bacteria in Atg16L1-dependent intestinal disease.

描述（由申请人提供）：我们的长期目标是了解遗传易感性和环境因素如何结合联合收割机介导炎症性肠病。Atg 16 L1和Nod 2是两个克罗恩病易感基因，由于其在先天免疫防御细菌中的关键功能而受到广泛关注。虽然Atg 16 L1在自噬中的重要作用和Nod 2在细菌识别中的重要作用已经被证明，但现在很清楚，突变这些分子在细胞和整个生物体水平上都具有复杂和不可预料的后果。因此，至关重要的是，我们在肠道疾病的背景下检查这些易感基因，以解释最近的研究，揭示新的下游功能和途径。我们以前证明，Atg 16 L1突变小鼠（Atg 16 L1 HM）发展肠道异常时，感染小鼠诺如病毒MNV。这些异常包括当MNV感染的Atg 16 L1 HM小鼠被化学品DSS损伤时克罗恩病样病理的产生。值得注意的是，我们现在已经发现这些病理的发展取决于肠道细菌和Nod 2。当Atg 16 L1 HM小鼠用抗生素治疗或与Nod 2敲除小鼠杂交时，它们被保护免于由MNV和DSS治疗诱导的肠道疾病。鉴于目前在该领域的挑战，在定义Nod 2功能和巨大的兴趣，了解肠道细菌，我们将利用这些观察，以深入了解粘膜免疫和克罗恩病的发病机制。在这个提议中，我们将测试一个模型，其中Nod 2感知特定的肠道细菌来介导Atg 16 L1 HM小鼠的炎症。我们还将确定与克罗恩病相关的Nod 2移码突变（Nod 2fs）是否与Atg 16 L1突变存在下的Nod 2缺失相似或不同，因为这些信息对炎症性疾病中的基因-基因相互作用具有重要意义。我们将通过以下具体目标来解决这些问题：（1）确定负责Atg 16 L1 HM小鼠中克罗恩病样病理的Nod 2信号通路，（2）定义Atg 16 L1 HM小鼠中疾病所需的特定细菌种群，以及（3）比较Nod 2缺失和Nod 2fs表达在肠道炎症中的作用。我们有一个独特的机会来表征两个非常感兴趣的易感基因和一个多击疾病模型中的肠道细菌植物群，该模型重现了与患者中观察到的病理相似的病理。

DESCRIPTION (provided by applicant): Our long-term goal is to understand how genetic susceptibility and environmental factors combine to mediate inflammatory bowel disease. Atg16L1 and Nod2 are two Crohn's disease susceptibility genes that have received much attention because of their critical function in innate immune defense against bacteria. While an essential role for Atg16L1 in autophagy and Nod2 in bacterial recognition have been demonstrated, it is now clear that mutating these molecules have complex and unanticipated consequences at both the cellular and whole organism level. Therefore, it is critical that we examine these susceptibility genes in the context of intestinal disease to interpret the recent studies that are revealing new downstream functions and pathways. We previously demonstrated that Atg16L1 mutant mice (Atg16L1HM) develop intestinal abnormalities when infected with the mouse norovirus MNV. These abnormalities include the generation of Crohn's-like pathologies when MNV-infected Atg16L1HM mice are injured with the chemical DSS. Remarkably, we have now found that development of these pathologies depends on both commensal bacteria and Nod2. When Atg16L1HM mice are treated with antibiotics or crosed to Nod2 knockout mice, they are protected from intestinal disease induced by MNV and DSS treatment. Given the current challenge in the field in defining Nod2 function and the great interest in understanding commensal bacteria, we will take advantage of these observations to gain insight into mucosal immunity and Crohn's disease pathogenesis. In this proposal, we will test a model in which Nod2 senses specific intestinal bacteria to mediate inflammation in Atg16L1HM mice. We will also determine if the Nod2 frameshift mutation (Nod2fs) associated with Crohn's disease is similar or distinct to Nod2 deletion in the presence of Atg16L1 mutation since this information will have important implications for gene-gene interactions in inflammatory diseases. We will address these issues with the following specific aims: (1) Identify the Nod2 signaling pathway that is responsible for Crohn's-like pathologies in Atg16L1HM mice, (2) Define the specific bacterial population required for disease in Atg16L1HM mice, and (3) Compare the effect of Nod2 deletion and Nod2fs expression in intestinal inflammation. We have a unique opportunity to characterize two susceptibility genes of great interest and the commensal bacterial flora in a multi-hit disease model that recreates pathologies similar to those observed in patients.