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

定义 Nod2 和细菌在 Atg16L1 依赖性肠道疾病中的作用。

• 批准号: 8785508
• 负责人: Ken Hashigiwa Cadwell
• 金额: $ 8.85万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8785508
• 关键词: Address; Adolescent; Antibiotics; Attention; Autophagocytosis; Bacteria; Biochemical; Biological Assay; Biological Models; Chemical Injury; Chemicals; Child; Complex; Crohn' s disease; Degradation Pathway; Dependence; Development; Disease; Disease model; Disease susceptibility; Environmental Risk Factor; Etiology; Frameshift Mutation; Generations; Genes; Genetic Predisposition to Disease; Germ-Free; Goals; Grant; Human; Immune; Immunity; Incidence; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Interferons; Intestinal Diseases; Intestines; Knockout Mice; Life; Ligands; Mediating; Modeling; Mucosal Immunity; Mus; Mutant Strains Mice; Mutate; Mutation; Norovirus; Organ; Pathogenesis; Pathology; Pathway interactions; Patients; Phosphotransferases; Population; Production; Reactive Oxygen Species; Reporting; Research; Role; Side; Signal Pathway; Signal Transduction; Susceptibility Gene; Testing; Tissues; Ulcer; Whole Organism; cell type; commensal microbes; cytokine; disability; experience; gene function; gene interaction; improved; in vivo; injured; insight; interest; loss of function; mouse model; pathogenic bacteria; prevent; response; sensor

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.

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联合介导炎症性肠病。Atg16L1和Nod2是克罗恩病的两个易感基因，因其在先天免疫防御细菌中的关键作用而受到广泛关注。虽然Atg16L1在自噬和Nod2在细菌识别中的重要作用已经被证明，但现在很清楚，这些分子的突变在细胞和整个生物体水平上都具有复杂和意想不到的后果。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，以解释最近揭示新的下游功能和途径的研究。我们之前证明，Atg16L1突变小鼠（Atg16L1）在感染小鼠诺如病毒MNV后出现肠道异常。这些异常包括当mnv感染的Atg16L1HM小鼠用化学物质DSS损伤时产生的克罗恩病样病理。值得注意的是，我们现在已经发现这些病理的发展取决于共生菌和Nod2。当Atg16L1HM小鼠用抗生素治疗或与Nod2敲除小鼠杂交时，它们可以免受MNV和DSS治疗诱导的肠道疾病。鉴于目前在定义Nod2功能方面的挑战以及对了解共生菌的极大兴趣，我们将利用这些观察结果来深入了解粘膜免疫和克罗恩病的发病机制。在本课题中，我们将在Atg16L1HM小鼠中测试Nod2感知特异性肠道细菌介导炎症的模型。我们还将确定与克罗恩病相关的Nod2移码突变（Nod2fs）是否与存在Atg16L1突变的Nod2缺失相似或不同，因为这一信息将对炎症性疾病中的基因-基因相互作用具有重要意义。我们将以以下具体目标来解决这些问题：(1)确定导致Atg16L1HM小鼠克罗恩病样病理的Nod2信号通路；(2)确定Atg16L1HM小鼠疾病所需的特定细菌群；(3)比较Nod2缺失和Nod2fs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种非常感兴趣的易感基因和共生菌群在一个多打击疾病模型中，重现类似于在患者中观察到的病理。