The Role of Interleukin 23 In Colitis Associated Cancer

描述（由申请人提供）：结肠炎相关癌（CAC）是炎症性肠病（IBD）最致命和最具破坏性的并发症。由于没有有效的预防或治疗CAC的策略，了解IBD如何诱导CAC是很重要的。细胞因子是炎症的小蛋白介质，有助于IBD的发展，也可能表现出促进肿瘤的特性。本项目主要研究白细胞介素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，我研究了细胞因子生物学的不同方面以及细胞因子在炎症、自身免疫和癌症中的作用。长期以来，我们的实验室一直使用偶氮甲烷+DSS诱导的CAC小鼠模型来模拟人类CAC的发展。利用这个模型，我们的实验室已经证明了转录因子NF-B与肿瘤发生之间的机制联系。由于对细胞因子如何促进癌症有长期的兴趣，我一直在寻找促炎细胞因子，其表达受NF-B控制，介导炎症对CAC的影响。与NF-B本身的整体抑制相比，这些细胞因子是更好的治疗靶点。我的初步数据表明IL-23在CAC中起重要作用。我假设IL-23通过激活几种途径来增加肿瘤的多样性和生长，这些途径维持上皮细胞和恶性细胞的慢性炎症和促生存途径，最终促进肿瘤的形成和生长。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）：评价IL-23在CAC发生、生长和进展中的作用。探讨IL-23在CAC - aim中作用的分子机制。探讨不同IL-23应答细胞类型在CAC肿瘤发生中的作用。研究不同的IL-23依赖性通路（IL-17和IL-22）在CAC肿瘤发生中的作用[5]。确定IL-23在CAC肿瘤发生不同阶段的作用及其遗传或药物阻断的后果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，并确定IL-23作为肠道炎症和CAC肿瘤发展的主要调节剂。如果证实IL-23对IBD和癌症的发展都有帮助，这种细胞因子将代表一个有吸引力的靶点，用于特异性治疗或预防CAC和IBD。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: The most serious complication of inflammatory bowel disease (IBD) is the development of colitis associated colon cancer (CAC), which happens in up to 20% of IBD patients and results in over 50% mortality. The regulation of inflammation involves many small proteins known as cytokines and my preliminary data suggests that the cytokine called IL-23 warrants detailed investigation, as its absence or inactivation in mice renders them resistant to CAC. I will study the role of IL-23 in CAC and determine the molecular mechanism of its action, with the aim of providing evidence that its inhibition can be used to prevent or treat CAC in IBD patients.