Regulation of intestinal inflammation and tumorigenesis by Nlrp6

Nlrp6 对肠道炎症和肿瘤发生的调节

基本信息

批准号：
8436792
负责人：
GRACE Y. CHEN
金额：
$ 32.27万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-01-18 至 2017-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8436792
关键词：
Adaptor Signaling Protein Affect Anti-Inflammatory Agents Aspirin Bacteria Bone Marrow Caspase-1 Cell Proliferation Cells Chemopreventive Agent Chronic Colitis Colon Colon Carcinoma Colorectal Cancer Data Development Disease Epithelial Family Genetic Predisposition to Disease Germ-Free Goals Hematopoietic Human Immune Immune system Immunologic Receptors Incidence Individual Inflammation Inflammatory Bowel Diseases Inflammatory disease of the intestine Injury Interleukin-10 Interleukin-18 Intestinal Cancer Intestinal Neoplasms Intestines Lead Macromolecular Complexes Malignant Neoplasms Mediating Mediator of activation protein Mus Obesity Pattern Pattern recognition receptor Play Polyps Population Predisposition Premalignant Production Property Regulation Role Signal Pathway Signal Transduction Source Testing Toll-like receptors Tumor Suppression Tumor Suppressor Proteins Tumorigenicity United States Woman cancer chemoprevention cancer risk carcinogenesis cell type colon carcinogenesis commensal microbes disorder risk gut microbiota high risk intestinal homeostasis member men microbiome mouse model novel novel strategies pathogenic bacteria public health relevance receptor repaired tumor tumorigenesis tumorigenic

项目摘要

DESCRIPTION (provided by applicant): Colorectal cancer is the third most common cancer in both men and women in the United States. The highest risk groups for developing colon cancer are those with a genetic predisposition and those with inflammatory bowel disease. For individuals with inflammatory bowel disease, the risk correlates with extent and duration of inflammation affecting the colon and can be increased 5- to 15-fold compared to normal individuals. Mouse models of inflammation-related colon cancer have demonstrated that intestinal bacteria and the host immune system can regulate intestinal inflammation and carcinogenesis. In particular, members of the Nod-like receptor family have emerged as important players in the development of intestinal inflammation and cancer. NLRs are intracellular pattern-recognition receptors that are involved in the sensing of both pathogenic and commensal bacteria within the gut. We have recently identified a relatively unknown member of the NLR family, Nlrp6, which is important for intestinal homeostasis and tumor suppression during chronic injury and inflammation within the colon. However, the mechanism by which Nlrp6 reduces tumor development and inflammation in the colon remains to be elucidated. We hypothesize that Nlrp6 modulates susceptibility to intestinal inflammation and tumorigenesis by regulating the composition of the gut microbiota and the production of IL-18. Our specific aims are: (1) to determine the importance of Nlrp6 in regulating the gut microbiome to increase susceptibility to colonic inflammation and cancer, (2) to identify the cell type that Nlrp6 functions in to suppress tumorigenesis, and 3) to understand the role of IL-18 in Nlrp6-mediated tumor suppression. The long-term goal of these studies is to increase our understanding of how interactions between NLRs and the gut microbiota regulate colon carcinogenesis, which may lead to novel chemopreventive strategies for colon cancer involving the manipulation of the intestinal bacteria and/or modulation of NLR signaling pathways.

描述（由申请人提供）：大肠癌是美国男性和女性中第三大常见的癌症。发生结肠癌的最高风险组是患有遗传易感性的患者和患有炎症性肠病的患者。对于患有炎症性肠病的个体，风险与影响结肠的炎症程度和持续时间相关，与正常人相比可以增加5至15倍。与炎症相关结肠癌的小鼠模型表明，肠道细菌和宿主免疫系统可以调节肠道炎症和致癌。特别是，在肠道炎症和癌症的发展中，点头样受体家族的成员已成为重要的参与者。 NLR是细胞内模式识别受体，与肠内致病性和共生细菌的感知有关。我们最近确定了NLR家族NLRP6的一个相对未知的成员，这对于慢性损伤和结肠内炎症期间肠内稳态和肿瘤抑制很重要。但是，NLRP6降低结肠中肿瘤发育和炎症的机制仍有待阐明。我们假设NLRP6通过调节肠道菌群的组成和IL-18的产生来调节对肠炎和肿瘤发生的敏感性。我们的具体目的是：（1）确定NLRP6在调节肠道微生物组以增加对结肠炎症和癌症的敏感性方面的重要性，（2）确定NLRP6在抑制肿瘤中起作用的细胞类型，以抑制肿瘤的发生，而3）以了解IL-18在NLRP6介导的tumor介导的tumor tumor的作用。这些研究的长期目标是提高我们对NLR与肠道微生物群之间的相互作用如何调节结肠癌的理解，这可能会导致针对结肠癌的新型化学预防策略，涉及操纵NLR信号传导途径的肠道细菌和/或调模。