Role of Stat3 in ETBF Mediated Colitis and Tumor Initiation

散发性结直肠癌(CRC)是美国第二大致死原因，是一种主要的 没有明确预防措施的健康问题。我工作的基础是发现 MIN(APC+/-)小鼠，感染人结肠共生肠毒素脆弱类杆菌(ETBF)， 发展结肠炎和快速结肠癌的形成部分依赖于 选择性Th17反应。新获得的初步数据表明，ETBF定植的致命性辐射 从IL17R-/-小鼠(IL17R KO仅限于上皮细胞)移植的MIN小鼠未能发育 3个月时出现肿瘤。这项建议的重点是确定共生菌群在ETBF诱导的IL-2中的作用。 17结肠炎与肿瘤发生。它旨在补充我正在进行的K08实验，该实验的核心是 评估关键的Th17途径转录因子STAT3在ETBF诱导的肿瘤发生中的作用。这样做的目的是 建议开始研究ETBF和/或共生生物如何对粘膜做出贡献 IL-17在ETBF结肠炎中的反应在体外，ETBF毒素BFT与特定的上皮细胞受体结合， 刺激细胞内黏附蛋白E-钙粘附素的裂解并触发信号的快速激活 转导途径和细胞通透性增加。在体内，ETBF增加屏障通透性， 允许共生细菌直接与粘膜免疫细胞相互作用。主要证据 这表明，在某些情况下，在上皮细胞屏障被打破后，共生细菌可以 通过Toll样受体(TLR)信号促进致癌的先天和获得性免疫反应。ETBF 最小CRC模型为理解特定的人类细菌(ETBF)提供了一种独特的方法 单独或与其他共生生物协同作用，能够诱导肿瘤发生。了解 微生物组在启动和促进儿童权利公约方面的总体作用是高度创新的。评选结果 本提案中的实验将作为R01提交的初步数据，重点是 IL-17在ETBF介导的肿瘤发生中的启动作用我的长期目标是了解 启动与人类结直肠癌相关的致瘤性IL-17反应。最近的研究表明，在早期 在人类CRC分期中，Th17签名与较差的预后相关。因此，机械论 了解这一点可能最终有助于免疫调节预防和治疗的发展 《儿童权利公约》战略。

Sporadic colorectal cancer (CRC), the second leading cause of death in the United States, is a major public health problem for which there are no clear preventive measures. The basis for my work is the discovery that Min (APC+/-) mice colonized with a human colonic commensal, enterotoxigenic Bacteriodes fragilis (ETBF), develop colonic inflammation and rapid colon tumor formation that are partly dependent on a predominant and selective Th17 response. Newly acquired preliminary data demonstrate that ETBF-colonized lethally irradiated Min mice with transplanted marrow from IL17R-/- mice (IL17R KO exclusively on epithelial cells) fail to develop tumors at 3 months. This proposal focuses on defining the contribution of commensal flora in ETBF-induced IL- 17 colitis and tumorigenesis. It is intended to complement my ongoing K08 experiments, which center on evaluating Stat3, a key Th17 pathway transcription factor, in ETBF-induced tumorigenesis. The goal of this proposal is to begin to investigate how ETBF and/or commensal organisms contribute to the mucosal IL-17 response in ETBF colitis. In vitro, the ETBF toxin, BFT, binds to a specific epithelial cell receptor, stimulates cleavage of the intracellular adhesion protein E-cadherin and triggers rapid activation of signal transduction pathways and increased cellular permeability. In vivo, ETBF increases barrier permeability, permitting the commensal bacteria to directly interact with the mucosal immune cells. Prevailing evidence suggests that, under certain contexts, after a breach in the epithelial cell barrier, commensal bacteria can promote oncogenic innate and adaptive immune responses via toll like receptor (TLR) signaling. The ETBF Min model of CRC provides a unique approach for understanding how a specific human bacterium (ETBF) alone or in concert with other commensal organisms, is able to induce tumorigenesis. Understanding the overall role of the microbiome in initiation and promotion of CRC is highly innovative. The results of the experiments in this proposal will serve as preliminary data for an R01 submission focused on mechanisms of IL-17 initiation in ETBF-mediated tumorigenesis. My long-term goal is to understand the mechanism of initiation of the oncogenic IL-17 response associated with human CRC. Recent studies demonstrate, in early stage human CRC, a Th17 signature is associated with worse prognosis. Therefore, mechanistic understanding may ultimately allow for development of immune modulating prevention and treatment strategies for human CRC.