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

描述(申请人提供)：患有炎症性肠病的患者患结肠癌的风险大大增加。从慢性结肠炎到结肠癌的发生尚不完全清楚，但可能与肠道微生物群的异常免疫反应有关，并可能与炎症反应过程中产生的活性氧物种、促炎细胞因子、抗凋亡因子和促进血管生成的信号有关，这些都有助于肿瘤的发生。这项建议的目标是使用一种小鼠模型来研究免疫受体Nod1在炎症相关结肠肿瘤发生中的作用。小鼠模型中，一次注射致癌物，然后多次注射含有葡聚糖硫酸钠(DSS)的水，后者会导致结肠炎。Nod1是先天性免疫系统的一个组成部分，它识别细菌中发现的肽聚糖部分，包括肠道微生物区系中的那些。初步数据表明，肠道微生物区系的Nod1信号可以在慢性炎症的背景下保护结肠肿瘤的发展。这种保护作用背后的机制尚不清楚，但我们的数据表明，Nod1受体和肠道微生物区系之间的相互作用对于维持肠道内环境稳定和抑制肿瘤非常重要。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增加了，脂联素是一种主要来自脂肪组织的炎症介质，也被证明在化学诱导的结肠炎的发展中也是重要的。因此，这项建议的具体目的是：1)阐明Nod1信号预防结肠癌发生和发展的机制，2)研究脂肪细胞因子脂联素在Nod1基因敲除小鼠慢性炎症期间对肿瘤形成的易感性中的作用，以及3)确定肠道微生物在Nod1介导的肿瘤抑制中的重要性。拟议的实验将提供更深层次的理解，了解肠道微生物区系和天然免疫系统之间的相互作用如何强烈影响结肠炎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临床策略奠定基础，该策略涉及操纵Nod1信号来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.