Role of the immune receptor Nod1 in inflammation-associated colon tumorigenesis

描述（由申请人提供）：炎症性肠病患者发生结肠癌的风险显著增加。从慢性结肠炎到结肠癌发生的事件尚不完全清楚，但可能与对肠道微生物菌群的异常免疫反应以及随后在炎症反应期间产生活性氧、促炎细胞因子、抗凋亡因子和血管生成促进信号有关，这些都有助于肿瘤发生。该提案的目标是使用小鼠模型研究免疫受体Nod1在炎症相关结肠肿瘤发生中的作用，该模型涉及单次注射致癌物质，然后多轮含有葡聚糖硫酸钠（DSS）的水，这会导致结肠炎。Nod1是先天免疫系统的一个组成部分，识别细菌中发现的肽聚糖部分，包括肠道微生物群的肽聚糖部分。初步数据表明，肠道微生物群的Nod1信号传导可以防止慢性炎症环境中结肠肿瘤的发展。这种保护作用背后的机制尚不清楚，但我们的数据表明，Nod1受体和肠道微生物群之间的相互作用对于维持肠道稳态和肿瘤抑制非常重要。与野生型相比，Nod1基因敲除小鼠的脂肪细胞因子脂联素的基础水平也有所增加，脂联素是一种主要来源于脂肪组织的炎症介质，在化学诱导的结肠炎的发展中也很重要。因此，本提案的具体目的是：1）阐明Nod1信号传导保护结肠肿瘤起始和进展的机制，2）检查脂肪细胞因子脂联素在Nod1敲除小鼠对慢性炎症期间肿瘤形成的易感性中的作用，以及3）确定肠道微生物群落在Nod1介导的肿瘤抑制中的重要性。拟议的实验将更深入地了解肠道微生物群和先天免疫系统之间的相互作用如何强烈影响结肠炎症的发展和随后的肿瘤发生。此外，拟议的研究将有助于为开发一种临床策略奠定基础，该策略涉及操纵Nod1信号传导以预防人类炎症相关结肠癌。

DESCRIPTION (provided by applicant): Patients with inflammatory bowel disease have a substantially increased risk of developing colon cancer. The events that lead from chronic colitis to colon carcinogenesis are not fully understood, but are likely related to an abnormal immune response to the gut microflora and subsequent production of reactive oxygen species, pro-inflammatory cytokines, anti-apoptotic factors, and angiogenic promoting signals during the inflammatory response, that are all conducive to tumorigenesis. The goal of this proposal is to investigate the role of the immune receptor Nod1 in inflammation-associated colon tumorigenesis using a mouse model that involves a single injection of a carcinogen followed by multiple rounds of water containing dextran sulfate sodium (DSS), which causes colitis. Nod1 is a component of the innate immune system that recognizes peptidoglycan moieties found in bacteria, including those of the gut microbiota. Preliminary data suggest that Nod1 signaling by the gut microbiota protects against the development of colon tumors in the setting of chronic inflammation. The mechanism behind this protective effect is unknown, but our data suggest that an interaction between the Nod1 receptor and the gut microbiota is important for maintenance of intestinal homeostasis and tumor suppression. Nod1 knockout mice, compared to wildtype, also have increased basal levels of the adipocytokine, adiponectin, an inflammatory mediator derived primarily from adipose tissue that has also been shown to be important in the development of chemically-induced colitis. Thus, the specific aims of this proposal are: 1) to elucidate the mechanism by which Nod1 signaling protects against colon tumor initiation and progression, 2) to examine the role of the adipocytokine, adiponectin, in the susceptibility of Nod1 knockout mice to tumor formation during chronic inflammation, and 3) to determine the importance of the intestinal microflora in Nod1-mediated tumor suppression. The proposed experiments will provide a deeper understanding of how interactions between the gut microbiota and the innate immune system strongly influence the development of colonic inflammation and subsequent tumorigenesis. In addition, the proposed research will help lay a foundation in the development of a clinical strategy that involves the manipulation of Nod1 signaling to prevent inflammation-associated colon cancer in humans.