Role of Stat3 in Colonic Inflammation

描述（由申请人提供）：炎症性肠病（IBD）影响美国约140万人。IBD的发病机制被认为涉及对遗传易感宿主的结肠植物群的过度免疫应答。当IBD（溃疡性结肠炎或克罗恩病）影响结肠和/或直肠时，患者发生结肠炎相关性结直肠癌的风险显著升高。在全结肠炎超过20年的患者中，癌症的风险接近20%。虽然结肠上皮细胞的遗传和表观遗传改变在结肠炎相关癌症中是不可避免的，但是什么触发了结肠上皮细胞的致癌转化却知之甚少。我们发现，Min（APC）小鼠殖民与人类结肠直肠，肠致炎性脆弱拟杆菌（ETBF）表现出显着的结肠炎症和快速结肠肿瘤的形成依赖于，部分，在结肠上皮细胞和免疫细胞的信号转导和转录激活因子3（Stat 3）的早期激活的主要和选择性的Th 17反应。这些结果支持了以下假设：微生物群可以沉淀在IBD的早期肿瘤变化中重要的特异性粘膜信号传导和免疫应答。我们进一步假设，Stat 3，一个关键的致癌转录调节因子，是上皮和粘膜免疫信号传导的协调调节因子，对结肠炎症和最终的肿瘤发生至关重要。本项目的目标是：1.为了确定ETBF感染小鼠中不同细胞类型（淋巴细胞、结肠上皮细胞和骨髓细胞）中Stat 3的激活如何促成结肠炎[原文如此]和2.确定与对照组相比，发生异型增生和/或结肠炎相关癌症的IBD患者的粘膜免疫特征（Th 1/Th 17平衡）。这些整合的小鼠和人体实验将在细菌发病机理专家Cynthia Sears博士和肿瘤免疫学专家Drew Pardoll博士的指导下完成，将为申请人提供最先进的发病机理和免疫学研究方法的实践经验。为了填补她的知识空白，申请人设计了免疫学和转化研究设计的补充教学计划。通过完成本职业发展计划获得的实践和教学经验将使申请人能够在未来五年内过渡到独立调查员。 公共卫生相关性：炎症性肠病（IBD）影响美国约140万人。当IBD（溃疡性结肠炎或克罗恩病）影响结肠和/或直肠时，患者患结直肠癌的风险显著升高。在全结肠炎超过20年的患者中，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.