Role of Stat3 in Colonic Inflammation

描述（由申请人提供）：炎症性肠病（IBD）在美国影响约140万人。IBD的发病机制被认为与易感宿主对结肠菌群的过度免疫反应有关。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结直肠癌的风险明显更高。在超过20年的全结肠炎患者中，癌症风险接近20%。尽管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，但引发结肠上皮细胞癌性转化的原因尚不清楚。我们发现，人类结肠共生的产肠毒素脆弱杆菌（ETBF）定殖的Min （APC）小鼠表现出明显的结肠炎症和快速的结肠肿瘤形成，部分依赖于结肠上皮细胞和免疫细胞中信号转导和转录激活因子3 （Stat3）的早期激活的显性和选择性Th17反应。这些结果支持了微生物群可以沉淀特异性粘膜信号和免疫反应的假设，这些信号和免疫反应在IBD早期肿瘤变化中很重要。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，对结肠炎症和最终的肿瘤发生至关重要。这个项目的目标是：1。在感染etbf的小鼠中，确定Stat3在不同细胞类型（淋巴细胞、结肠上皮细胞和骨髓细胞）中的激活如何导致结肠炎[原文如此]。定义与对照组相比，发生发育不良和/或结肠炎相关癌症的IBD患者的粘膜免疫谱（Th1/Th17平衡）。这些综合小鼠和人体实验将在细菌发病机制专家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制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。通过完成此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。

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.