The Role of Interleukin 23 In Colitis Associated Cancer

摘要（摘要） 结肠炎相关癌（CAC）是炎症性肠病最致命和最具破坏性的并发症 疾病（IBD）。由于没有有效的预防或治疗CAC的策略，重要的是要了解IBD如何 诱发CAC。细胞因子是炎症的小蛋白介质，有助于IBD 发展，并且还可能表现出肿瘤促进特性。该项目的重点是 白细胞介素23（IL-23）在慢性炎症和CAC肿瘤发生中的调节。在过去的8年里，我 致力于细胞因子生物学的不同方面以及细胞因子在炎症，自身免疫和 癌长期以来，本实验室采用氧化偶氮甲烷+DSS诱导的CAC小鼠模型来模拟CAC 人类的发展。使用这个模型，我们的实验室已经证明了 转录因子NF-B与肿瘤发生。我对细胞因子如何促进癌症有着长期的兴趣， 我一直在寻找促炎细胞因子，其表达受NF-B控制，介导效应 炎症的症状这样的细胞因子与对细胞因子的整体抑制相比是更好的治疗靶标。 NF-B本身。我的初步数据表明IL-23在CAC中起重要作用。我假设IL-23 通过激活几种维持慢性炎症的途径增加肿瘤的多样性和生长 以及上皮细胞和恶性细胞中的促生存途径，并最终增强肿瘤形成， 增长为了研究IL-23在CAC中的作用，我将使用各种基因修饰的小鼠和CAC的小鼠模型。我 将追求5个独立的目标（2个目标在指导阶段，3个目标在独立阶段的 奖项）： 目标1.评价IL-23在CAC发生、生长和进展中的作用 目标2。探讨IL-23在CAC中作用的分子机制 目标3。检查不同IL-23应答细胞类型在CAC肿瘤发生中的作用 目标4。检查不同IL-23依赖性途径（IL-17和IL-22）在CAC中的作用 肿瘤发生 目标5。确定IL-23在CAC肿瘤发生的不同阶段的作用以及 基因或药物阻断 本研究的长期目标是剖析CAC肿瘤发生所需的细胞因子网络， 确立IL-23作为肠道炎症和CAC肿瘤发生主要调节因子。如果证明IL-23 是IBD和癌症发展的工具，这种细胞因子将代表一个有吸引力的目标， 特异性治疗或预防CAC和IBD。

Abstract (Summary) Colitis associated cancer (CAC) is the most deadly and devastating complication of inflammatory bowel disease (IBD). With no effective preventive or treatment strategy for CAC it is important to understand how IBD induces CAC. Cytokines are small protein mediators of inflammation that are instrumental for IBD development, and may also exhibit tumor-promoting properties. This project is focused on the role of Interleukin 23 (IL-23) in regulation of chronic inflammation and CAC tumorigenesis. During the last 8 years I worked on different aspects of cytokine biology and the role of cytokines in inflammation, autoimmunity and cancer. For a long time our lab has used a azoxymethane+DSS induced CAC mouse model to mimic CAC development in humans. Using this model, our lab has shown a mechanistic connection between the transcription factor NF-B and tumorigenesis. Having long-term interest in how cytokines promote cancer, I have searched for pro-inflammatory cytokines, whose expression is controlled by NF-B, which mediate effects of inflammation on CAC. Such cytokines are better targets for therapy in comparison with global inhibition of NF-B itself. My preliminary data suggests an important role for IL-23 in CAC. I hypothesize that IL-23 increases tumor multiplicity and growth by activating several pathways, which maintain chronic inflammation and pro-survival pathways in epithelial and malignant cells, and eventually enhance tumor formation and growth. To study the role of IL-23 in CAC I will use various gene modified mice and a mouse model of CAC. I will pursue 5 separate Aims (2 Aims during Mentored phase and 3 Aims during Independent phase of the award): Aim1. Evaluate the role of IL-23 in CAC development, growth and progression Aim2. Explore molecular mechanisms of IL-23 action in CAC Aim3. Examine the contribution of different IL-23 responsive cell types in CAC tumorigenesis Aim4. Examine the contribution of different IL-23 dependent pathways (IL-17 and IL-22) in CAC tumorigenesis Aim 5. Determine the role of IL-23 at different stages of CAC tumorigenesis and the consequences of its genetic or pharmacological blockade The long-term objective of this study is to dissect a cytokine network required for CAC tumorigenesis and to establish IL-23 as master regulator of intestinal inflammation and CAC tumord evelopment. If proven that IL-23 is instrumental for both IBD and cancer development, this cytokine would represent an attractive target for specific therapy or prevention of CAC and IBD.