Modulation of colitis-associated cancer by cyclosporine A

环孢菌素 A 对结肠炎相关癌症的调节

• 批准号: 8787456
• 负责人: DONALD A COHEN
• 金额: $ 7.51万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8787456
• 关键词: Acute; Affect; Allogenic; Animal Diseases; Animal Model; Animals; Azoxymethane; Biological Models; Bone Marrow Transplantation; Calcineurin; Characteristics; Chronic; Clinical; Colitis; Colon Carcinoma; Colonic Neoplasms; Colorectal Cancer; Crohn' s disease; Cyclosporine; Development; Disease; Dose; Epithelial Physiology; Exhibits; Experimental Models; Frequencies; General Population; Health; Immune; Immunosuppressive Agents; Inflammation; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Intestinal Neoplasms; Intestines; Large Intestine; Lead; Malignant Neoplasms; Modeling; Mus; Neoplasm Metastasis; Patients; Permeability; Pharmaceutical Preparations; Population; Refractory; Risk; Role; Severities; Small Intestines; Sodium Dextran Sulfate; Steroids; Syndrome; System; Testing; Therapeutic; Therapeutic immunosuppression; Toxic effect; Ulcerative Colitis; cancer cell; cancer risk; colitis associated cancer; effective therapy; feeding; gut microbiota; intestinal epithelium; intestinal homeostasis; member; microbiome; mouse model; pre-clinical; response; tumor; tumor growth; tumor progression

DESCRIPTION (provided by applicant): Patients with inflammatory bowel disease (IBD) develop malignancies of the intestinal tract at an increased frequency compared to the normal population. This is thought to be due, in part, to the chronic inflammation associated with this debilitating disease. Cyclosporine A (CsA) is an effective treatment for patients with severe, steroid-refractory IBD, especially ulcerative colitis (UC). However, the use of CsA in animal models has been associated with enhanced spread of colorectal cancer cells. We have shown that treatment of bone marrow transplanted (BMT) mice with CsA leads to a colitis-like disease similar to other models of IBD. Importantly, recent studies have demonstrated a role for the inflammasome, in intestinal homeostasis and the development of colitis-associated intestinal tumors. IBD patients have decreased inflammasome activity which may contribute to the development of clinical disease and animals with deficiencies in the inflammasome develop enhanced colitis and colon tumors. We have documented that CsA-treatment of BMT mice inhibited the activation of the inflammasome and may have participated in the development of colitis-like disease, making suspect the clinical use of CsA in refractory IBD. Given these findings two specific aims will be proposed to test the hypothesis that cyclosporine treatment will alter intestinal homeostasis via inhibition of inflammasome function, resulting in enhanced tumor growth in the azoxymethane (AOM)/dextran sulfate sodium (DSS) model of colitis-associated colon cancer (CAC). Aim 1 will determine if treatment of AOM/DSS- treated animals with a therapeutic dose of CsA will enhance the severity of colitis and the development of CAC. Inflammasome expression and activity will be determined in CsA-treated mice after induction of AOM/DSS CAC. Preliminary results show that CsA therapy inhibits intestinal barrier function in BMT mice. Thus, we propose that intestinal damage which occurs during the induction of AOM/DSS also will be prolonged by CsA therapy. Aim 2 will test the hypothesis that CsA-induced alterations in intestinal epithelium will lead to increased permeability and decreased barrier function via inhibition of inflammasome function, which may contribute to increased colitis and development of CAC. As patients with IBD have reduced inflammasome activity, the potential exists that the use of CsA to treat refractory IBD may enhance development of the disease by further reducing inflammasome function, leading to and enhanced risk of CAC. It is imperative to analyze the effects of immunosuppressive therapy on intestinal damage, induction of colitis and CAC in model animal systems to understand the risk of CsA therapy in the treatment of IBD.

描述(申请人提供)：与正常人群相比，炎症性肠病(IBD)患者发生肠道恶性肿瘤的频率更高。这被认为部分是由于与这种令人衰弱的疾病相关的慢性炎症。环孢素A(CsA)是治疗激素难治性重症IBD，尤其是溃疡性结肠炎(UC)的有效药物。然而，在动物模型中使用CsA与促进结直肠癌细胞的扩散有关。我们已经证明，用CsA治疗骨髓移植(BMT)小鼠会导致一种类似于其他IBD模型的结肠炎样疾病。重要的是，最近的研究表明，炎性小体在肠道内稳态和结肠炎相关性肠道肿瘤的发展中发挥了作用。IBD患者的炎性小体活性降低，这可能有助于临床疾病的发展，而炎性小体缺乏的动物会发展为结肠炎和结肠肿瘤。我们已经证明CsA对BMT小鼠的治疗抑制了炎症小体的激活，并可能参与了结肠炎样疾病的发展，这使得CsA在难治性IBD中的临床应用受到怀疑。鉴于这些发现，将提出两个具体目标来检验环孢素治疗将 通过抑制炎症体功能改变肠道内环境平衡，导致在偶氮甲烷(AOM)/葡聚糖硫酸钠(DSS)结肠炎相关结肠癌(CAC)模型中促进肿瘤生长。目的1将确定用治疗量的环孢素A治疗AOM/DSS的动物是否会增加结肠炎的严重性和CAC的发展。在诱导AOM/DSS CAC后，将测定CsA处理的小鼠的炎症体的表达和活性。初步结果表明，CsA治疗抑制了骨髓移植小鼠的肠屏障功能。因此，我们认为在AOM/DSS诱导过程中发生的肠道损伤也将被CsA治疗延长。目的2验证环孢素A引起的肠道上皮细胞改变将通过抑制炎性小体功能导致通透性增加和屏障功能降低的假说，这可能是结肠炎增加和CAC发生的原因之一。由于IBD患者炎性小体活性降低，使用CsA治疗难治性IBD可能通过进一步降低炎性小体功能而促进疾病的发展，从而导致CAC和增加CAC的风险。为了了解CsA治疗IBD的风险，有必要在动物模型系统中分析免疫抑制治疗对肠道损伤、结肠炎和CAC的影响。