The Role of Interleukin 23 In Colitis Associated Cancer

白细胞介素 23 在结肠炎相关癌症中的作用

基本信息

批准号：
8572646
负责人：
Sergei I. Grivennikov
金额：
$ 4.74万
依托单位：
RESEARCH INST OF FOX CHASE CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-05-03 至 2013-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8572646
关键词：
Ablation Acute Adverse effects Affect African Anti-Tumor Necrosis Factor Therapy Asians Autoimmunity Award Azoxymethane Biology Cancer Model Carcinoma Cells Chronic Colitis Colon Carcinoma Colorectal Cancer Complication Cytokine Network Pathway Data Development Exhibits Gene-Modified Genetic Growth Growth and Development function Host Defense Human Incidence Inflammation Inflammation Mediators Inflammatory Inflammatory Bowel Diseases Inflammatory disease of the intestine Injury Interleukin-17 Interleukin-6 Investigation Life Style Malignant Epithelial Cell Malignant Neoplasms Mediating Mentors Modeling Molecular Mus Pathway interactions Patients Phase Population Prevention Prevention strategy Prevention therapy Production Property Proteins Regulation Research Resistance Role Severities Signal Pathway Signal Transduction Sodium Dextran Sulfate Staging TNF gene Time Tissues Tumorigenicity Work adenoma cancer diagnosis cancer therapy cell type colitis associated cancer cytokine in vivo interest interleukin-22 interleukin-23 mortality mouse model neoplastic cell prevent receptor tissue repair transcription factor treatment strategy tumor tumor growth tumorigenesis tumorigenic

项目摘要

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.

描述（由申请人提供）：与结肠炎相关的癌症（CAC）是炎症性肠病（IBD）最致命，毁灭性的并发症。没有有效的CAC预防或治疗策略，重要的是要了解IBD如何诱导CAC。细胞因子是炎症的小蛋白质介质，对IBD发育有用，也可能表现出肿瘤的特性。该项目的重点是白介素23（IL-23）在调节慢性炎症和CAC肿瘤发生的作用上。在过去的8年中，我从事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。很长一段时间以来，我们的实验室一直使用甲氧烷+DSS诱导的CAC小鼠模型来模仿人类的CAC发育。使用此模型，我们的实验室显示了转录因子NF-B和肿瘤发生之间的机械联系。我对细胞因子如何促进癌症具有长期兴趣，我搜索了促炎性细胞因子，其表达受NF-B的控制，NF-B介导了炎症对CAC的影响。与NF-B本身的全球抑制相比，这种细胞因子是治疗的更好靶标。我的初步数据表明IL-23在CAC中的重要作用。我假设IL-23通过激活多种途径来增加肿瘤的多样性和生长，这些途径在上皮细胞和恶性细胞中维持慢性炎症和促卵巢途径，并最终增强肿瘤的形成和生长。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的小鼠模型。我将追求5个单独的目标（在指导阶段的2个目标和奖励独立阶段的3个目标）：AIM1。评估IL-23在CAC开发，增长和进展AIM2中的作用。探索CAC AIM3中IL-23作用的分子机制。检查不同IL-23反应性细胞类型在CAC肿瘤发生AIM4中的贡献。检查不同IL-23依赖性途径（IL-17和IL-22）在CAC肿瘤发生的目标5中的贡献5。确定IL-23在CAC肿瘤发生的不同阶段的作用及其遗传或药理阻滞的后果，该研究的长期目标是将CAC构成量的cac tumorialsission和CAC的长期目标置于cac tumoriganty和cac的范围内。肿瘤逃避。如果证明IL-23对IBD和癌症发展具有重要作用，则该细胞因子将代表特定治疗或预防CAC和IBD的有吸引力的靶标。