The Role of Interleukin 23 In Colitis Associated Cancer

摘要(摘要) 结肠炎相关性癌症(CAC)是炎症性肠病最致命、最具破坏性的并发症。 疾病(IBD)。在没有有效的CAC预防或治疗策略的情况下，了解IBD如何 诱发CAC。细胞因子是炎症的小蛋白介质，在IBD中起重要作用 发展，也可能表现出促进肿瘤的特性。这个项目的重点是 白介素23(IL-23)在慢性炎症和CAC肿瘤发生中的调节作用在过去的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 癌症。长期以来，我们实验室一直使用偶氮甲烷+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 转录因子核因子-B与肿瘤发生。对细胞因子如何促进癌症有长期的兴趣，我 我一直在寻找促炎细胞因子，它们的表达受核因子-B的控制，而核因子-B是调节效应的 CAC上的炎症反应。这种细胞因子是更好的治疗靶点，而不是全局抑制 核因子-B本身。我的初步数据显示，IL-23在CAC中起着重要作用。我推测IL-23 通过激活几条维持慢性炎症的通路来增加肿瘤的多样性和生长 和在上皮细胞和恶性细胞中的促生存途径，最终促进肿瘤的形成和 成长。为了研究IL-23在CAC中的作用，我使用了各种基因修饰的小鼠和CAC的小鼠模型。我 将追求5个不同的目标(2个目标在指导阶段，3个目标在独立阶段 奖项)： 目的：1.评价IL-23在CAC发生、生长和发展中的作用 AIM2.IL-23在CAC中作用的分子机制探讨 Aim3.检测不同IL-23反应细胞类型在CAC肿瘤发生中的作用 目的：4.检测不同IL-23依赖途径(IL-17和IL-22)在CAC中的作用 肿瘤发生 目的5.确定IL-23在CAC发生的不同阶段中的作用及其后果 它的遗传或药理阻断 这项研究的长期目标是剖析CAC肿瘤发生所需的细胞因子网络，并 建立IL-23作为肠道炎症和CAC肿瘤发生的主要调节因子。如果被证实，IL-23 对IBD和癌症的发展都有帮助，这种细胞因子将是一个有吸引力的靶点 CAC和IBD的特定治疗或预防。

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.