The Roles of IBD Associated Genes ATG16L1 and TNFSF15 in Gut Mucosal Inflammation

描述(申请人提供)：炎症性肠病(IBD)是由易感基因、环境和粘膜免疫系统之间复杂的相互作用引起的。这些相互作用导致了对肠道微生物菌群的夸大免疫反应。随着高通量分子技术的出现，全基因组关联研究发现了一些与IBD相关的基因，包括细胞内模式识别传感器NOD2、自噬基因(ATG16L1和IRGM)和肿瘤坏死因子超家族成员15(TNFSF15)。最近的一些报道表明，ATG16L1和NOD2以共同的途径相互作用，影响微生物的处理，包括将细菌隔离到自噬体内，清除细胞内的细菌，以及抗原递呈。一些研究表明，TNFSF15由抗原提呈细胞(APC)表达，并通过增强Th1、Th17和Th2反应来决定慢性肠炎的严重程度。我们证明了多种致病细菌和共生细菌都能诱导APC中TNFSF15的表达。我们未发表的数据表明，TNFSF15的表达可以通过NOD2的激活和自噬的诱导而增加，这表明细菌加工在TNFSF15的诱导中起着重要的作用。这项研究的目的是探讨自噬依赖的细菌处理在诱导TNFSF15表达和调节肠道炎症中的机制(S)。我们将测试这一假设，即通过对细菌抗原的自噬处理导致肠道炎症加剧，微生物的自噬处理对于TNFSF15的最佳表达是重要的。此外，我假设较高水平的TL1A表达将放大炎症免疫反应，并加剧慢性肠炎的严重程度。以下具体目标将检验这一假设。特定目标1：确定有助于TNFSF15最佳表达的自噬途径中的步骤；特定目标2：ATG16L1和IRGM的CD基因变体与人APC中TNFSF15表达的相关性；特定目标3：确定上皮细胞、树突状细胞和巨噬细胞中的自噬在小鼠慢性结肠炎的发展和严重程度中的作用。这项研究的意义在于，它将使人们能够洞察肠道微生物群的粘膜免疫反应，从而可能导致新的IBD治疗方法。

DESCRIPTION (provided by applicant): Inflammatory bowel diseases (IBD) result from complex interactions between susceptibility genes, the environment, and the mucosal immune system. These interactions lead to an exaggerated immune response to the gut microbial flora. With the advent of high-throughput molecular technologies, genome wide association studies (GWAS) identified several IBD associated genes including intracellular pattern recognition sensor NOD2, autophagy genes (ATG16L1 and IRGM) and tumor necrosis factor superfamily member 15 (TNFSF15). Several recent reports show that ATG16L1 and NOD2 interact in a common pathway to affect microbial handling including sequestration of bacteria into autophagosomes, clearance of intracellular bacteria, and antigen presentation. Several studies have shown that TNFSF15 is expressed by antigen presenting cells (APC) and determines the severity of chronic gut inflammation by enhancing Th1, Th17 and Th2 responses. We demonstrated that a variety of bacteria, both pathogenic and commensal, can induce TNFSF15 expression in APC. Our unpublished data show that TNFSF15 expression can be increased by NOD2 activation and induction of autophagy, indicating an important role of bacterial processing in the induction of TNFSF15. The objective of this research proposal is to address the mechanism(s) of autophagy dependent bacterial handling in the induction of TNFSF15 expression and modulation of intestinal inflammation. We will test the hypothesis that autophagy handling of microbial organism is important for optimal TNFSF15 expression through autophagy processing of bacterial antigen leading to enhanced intestinal inflammation. Furthermore, I hypothesize that the higher level of TL1A expression will amplify inflammatory immune responses and exacerbate the severity of chronic intestinal inflammation. The following specific aims will test this hypothesis. Specific Aim 1: Determine the steps in the autophagy pathway that contribute to optimal expression of TNFSF15; Specific Aim 2: Correlate genetic CD variants of ATG16L1 and IRGM to TNFSF15 expression in human APC; Specific Aim 3: Determine the role of autophagy in epithelial cells, dendritic cells, and macrophage on the development and severity of murine chronic colitis. The significance of this research is that it will allow insight on mucosal immune responses to gut microflora that may lead to new IBD therapies.