Role of Stat3 in Colonic Inflammation

描述(申请人提供)：炎症性肠病(IBD)在美国影响大约140万人。IBD的发病机制被认为与遗传易感宿主对结肠菌群的过度免疫反应有关。当IBD，无论是溃疡性结肠炎还是克罗恩病，影响到结肠和/或直肠时，患者患结肠炎相关结直肠癌的风险明显更高。在患有泛结肠炎超过20年的患者中，患癌症的风险接近20%。虽然结肠上皮细胞的遗传和表观遗传学改变在结肠炎相关性癌症中是不可避免的，但触发结肠上皮细胞致癌转化的原因却知之甚少。我们发现，用人结肠共生肠毒素脆性杆菌(ETBF)定植的Min(APC)小鼠表现出显著的结肠炎和快速的结肠癌形成，部分依赖于主要的和选择性的Th17反应，并早期激活结肠上皮细胞和免疫细胞中的信号转导和转录激活因子3(STAT3)。这些结果支持这样的假设，即微生物区系可以沉淀特定的粘膜信号和免疫反应，这些信号和免疫反应在IBD的早期肿瘤性变化中至关重要。我们进一步假设，STAT3是一个关键的致癌转录调节因子，是上皮和粘膜免疫信号的协调调节因子，对结肠炎和最终肿瘤的发生至关重要。该项目的目标是：1.在ETBF感染的小鼠中，确定不同细胞类型(淋巴细胞、结肠上皮细胞和髓系细胞)中STAT3的激活如何促进肠炎[SIC]；2.确定与对照组相比，发展为异型增生和/或结肠炎相关癌症的IBD患者的粘膜免疫模式(Th1/Th17平衡)。这些综合的小鼠和人体实验将在细菌发病机制专家辛西娅·西尔斯博士和肿瘤免疫学专家德鲁·帕多尔博士的指导下完成，将为申请者提供最先进的发病机制和免疫学研究方法的实践经验。为了填补知识空白，申请者设计了免疫学和翻译研究设计方面的补充教学计划。通过完成这项职业发展计划获得的实践和教育经验将使申请者能够在未来五年内过渡到独立调查人员。 公共卫生相关性：炎症性肠病(IBD)影响着美国约140万人。当IBD，无论是溃疡性结肠炎还是克罗恩病，影响到结肠和/或直肠，患者患结直肠癌的风险明显更高。在患有泛结肠炎超过20年的患者中，患结直肠癌的风险接近20%。了解肠道炎症和结肠肿瘤之间的关系可能有助于确定预防IBD患者癌症和治疗结肠炎相关癌症的策略。

DESCRIPTION (provided by applicant): Inflammatory bowel disease (IBD) affects approximately 1.4 million people in the United States. The pathogenesis of IBD is thought to involve an exaggerated immune response to the colonic flora in the genetically susceptible host. When IBD, either ulcerative colitis or Crohn's disease, affects the colon and/or rectum, patients are at a signficantly [sic] higher risk of developing colitis associated-colorectal cancer. In patients with pancolitis for greater than 20 years the risk of cancer approaches 20%. Although colonic epithelial cell genetic and epigenetic alterations are inevitable in colitis associated cancer, what triggers colonic epithelia cell oncogenic transformation is poorly understood. We found that Min (APC ) mice colonized with an human colonic commensal, enterotoxigenic Bacteriodes fragilis (ETBF) demonstrate marked colonic inflammation and rapid colon tumor formation dependent, in part, on a predominant and selective Th17 response with early activation of signal transducer and activator of transcription 3 (Stat3) in colonic epithelial cells and immune cells. These results support the hypothesis that the microbiota can precipitate specific mucosal signaling and immune responses important in early neoplastic changes in IBD. We further hypothesize that Stat3, a key oncogenic transcriptional regulator, is a coordinate regulator of the epithelial and mucosal immune signaling and is critical to colon inflammation and, ultimately, tumorigenesis. The goals of this project are: 1. To define in ETBF-infected mice, how Stat3 activation in distinct cell types (lymphocytes, colonic epithelial cells and myeloid cells) contributes to coitis [sic] and 2. To define the mucosal immune profile (Th1/Th17 balance) in IBD patients who develop dysplasia and/or colitis-associated cancer compared to controls. These integrated mouse and human experiments, that will be completed under the mentorship of Dr. Cynthia Sears, expert in bacterial pathogenesis, and Dr. Drew Pardoll, expert in tumor immunology, will provide the applicant with practical experience in state of the art pathogenesis and immunology research methods. To complete gaps in her knowledge, the applicant has designed a complementary didactic program in immunology and translational research design. Together the practical and didactic experience gained by completing this career development plan will enable the applicant to transition to an independent investigator over the next five years. PUBLIC HEALTH RELEVANCE: Inflammatory bowel disease (IBD) affects approximately 1.4 million people in the United States. When IBD, either ulcerative colitis or Crohn's disease, affects the colon and/or rectum, patients are at a signficantly [sic] higher risk of developing colorectal cancer. In patients with pancolitis for greater than 20 years the risk of colorectal cancer approaches 20%. Understanding the relationship between intestinal inflammation and colonic neoplasia may help in identifying strategies for preventing cancer in IBD patients and for treating colitis associated cancers.