Eotaxin in Colitis and Colitis-Associated Carcinogenesis

结肠炎和结肠炎相关癌变中的嗜酸细胞趋化因子

• 批准号: 8542047
• 负责人: Lori A Coburn
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8542047
• 关键词: Accounting; Admission activity; Adoptive Transfer; Adult; Adverse effects; Affect; Age; American; Apoptosis; Arginine; Award; Azoxymethane; Biological Assay; Biological Markers; Body Weight decreased; CCL11 gene; CSF3 gene; Cationic Amino Acid Transporter 2; Chemotactic Factors; Childhood; Chronic; Citrobacter; Citrobacter rodentium; Clinical; Colitis; Colon; Colon Carcinoma; Colorectal Cancer; Crohn' s disease; Data; Development; Disease; Disease remission; Eotaxin; Epithelial; Epithelial Cells; Experimental Models; Gastritis; Granulocyte-Macrophage Colony-Stimulating Factor; Healthcare Systems; Helicobacter pylori; Histologic; Hospitalization; Human; Immune; Immune response; Immunosuppressive Agents; In Vitro; Infection; Infiltration; Inflammation; Inflammatory Bowel Diseases; Inflammatory Response; Injury; Lead; Length; Link; Location; Lung; Mediating; Mediator of activation protein; Meta-Analysis; Metabolism; Modeling; Modification; Morbidity - disease rate; Mus; Office Visits; Outpatients; Patients; Permeability; Phenotype; Physicians; Predisposing Factor; Probability; Publishing; Quality of life; Reporting; Risk; Role; Scientist; Serum; Severity of illness; Small inducible cytokine A24; Sodium Dextran Sulfate; Splenocyte; Supplementation; Symptoms; T-Lymphocyte; Time; Tissues; Training Support; Treatment Protocols; Ulcerative Colitis; United States National Institutes of Health; Urine; Veterans; Weight; Work; carcinogenesis; cell motility; chemokine; cohort; cytokine; eosinophil; eosinophilic inflammation; immune activation; injury and repair; insight; macrophage; mouse model; novel therapeutics; prospective; public health relevance; therapy development; tumor; tumorigenesis; uptake

DESCRIPTION (provided by applicant): With more than one million Americans affected, inflammatory bowel disease (IBD), consisting of ulcerative colitis (UC) and Crohn's disease, causes significant morbidity and can progress to colon cancer. While multiple predisposing factors have been identified, the cause or trigger for IBD remains unknown. Current treatment regimens for IBD are selected from an assortment of immunosuppressive agents, which can be complicated by multiple side effects and expense. In the search for new therapeutic options, including studies in vitro, in mouse models, and in a prospectively collected cohort of adult patients with UC, our human serum profiling data indicate that eotaxin-1 may be a biomarker of disease activity in UC. Eotaxin-1 (CCL11) is a chemoattractant for eosinophils. When the cytokine and chemokine profiles in this cohort of 40 controls and 137 UC patients were defined, there were 13 tissue cytokines and chemokines that were significantly elevated in the UC versus control patients, but out of a panel of 42 analytes, there were only 3 that were elevated in the serum: eotaxin-1, G-CSF, and GM-CSF. Of these, eotaxin-1 was the only analyte increased in both serum and tissue at all levels of disease severity. Increased eotaxin-1 has been shown in pediatric UC tissues, and has been linked to eosinophilic inflammation, but has not been previously investigated in a large, prospective adult UC cohort. Due to the novelty of this observation, studies of the role of eotaxin-1 in mouse models of colitis and colitis-associated carcinogenesis are the focus of this proposal. Along with the increased serum and tissue eotaxin-1, there is a significant increase in colonic tissue eosinophils in UC patients versus controls, and eosinophil counts correlated with tissue eotaxin-1 levels. Eotaxin-1 has been shown to be increased in dextran sulfate sodium (DSS) induced colitis by my collaborator, and we now show for the first time that eotaxin-1 is upregulated in: 1) Citrobacter rodentium-induced colitis tissues; 2) T cell transfer-induced colitis tissues; 3) tumor induced in the azoxymethane (AOM)-DSS model of colitis-associated carcinogenesis; and 4) macrophages or colonic epithelial cells activated with C. rodentium. However, eotaxin-1 is not increased in mouse Helicobacter pylori-induced gastritis tissues, indicating that this is not a non specific component of inflammation. Hypothesis: Eotaxin-1 is a key mediator of colitis and colitis-associated carcinogenesis via effects on macrophages and epithelial cells. The Specific Aims for this project are: 1. To determine the role of eotaxin-1 in the modulation of experimental colitis. We will utilize the C. rodentium infection model of colitis that involves immune activatio and the T cell transfer model of colitis that involves immune activation and epithelial damage. We will compare wild-type (WT) and eotaxin1-/- mice in the C. rodentium model, as well as eotaxin1+/+Rag2-/- and eotaxin1-/-Rag2-/- mice, with and without adoptive transfer of CD4+CD45RBhi effector T cells in the T cell transfer model. In each model of colitis the following will be assessed: clinical parameters, the colonic and systemic innate immune response focusing on macrophage phenotype and function, as well as epithelial function. 2. To determine the role of eotaxin-1 in the modulation of chronic colitis and colitis-associated carcinogenesis (CAC). Our preliminary data shows for the first time that colitis-associated tumors in the AOM-DSS model have increased eotaxin-1 levels. We will utilize the AOM-DSS model in WT and eotaxin1-/- mice to establish whether modification of the inflammatory response caused by deletion of eotaxin-1 can decrease the risk for CAC. In both chronic colitis (mice treated with multiple cycles of DSS) and colitis-associated tumorigenesis (mice treated with AOM followed by multiple cycles of DSS) the following will be assessed: clinical parameters including tumor size and multiplicity, colonic and systemic innate immune responses focusing on macrophage phenotype and function, as well as epithelial function, including in tumor and adjacent non-tumor tissues. These studies will provide new mechanistic insights into the role of eotaxin-1 in IBD and associated carcinogenesis.

描述（由申请人提供）： 炎症性肠病（IBD）由溃疡性结肠炎（UC）和克罗恩病（Crohn's disease）组成，有超过一百万的美国人受到影响，导致显著的发病率，并且可以进展为结肠癌。虽然已经确定了多种诱发因素，但IBD的原因或触发因素仍然未知。目前的IBD治疗方案是从各种免疫抑制剂中选择的，这些治疗方案可能会因多种副作用和费用而变得复杂。在寻找新的治疗选择，包括体外研究，在小鼠模型中，并在一个前瞻性收集的队列的成年患者与UC，我们的人血清分析数据表明，嗜酸性粒细胞趋化因子-1可能是一个生物标志物的疾病活动在UC。嗜酸性粒细胞趋化因子-1（CCL 11）是嗜酸性粒细胞的化学引诱物。当确定40例对照组和137例UC患者的细胞因子和趋化因子谱时，与对照组相比，UC患者中有13种组织细胞因子和趋化因子显著升高，但在42种分析物中，血清中仅3种升高：嗜酸性粒细胞趋化因子-1，G-CSF和GM-CSF。其中，嗜酸性粒细胞趋化因子-1是在所有疾病严重程度水平下血清和组织中增加的唯一分析物。在儿科UC组织中已显示出嗜酸性粒细胞趋化因子-1增加，并且与嗜酸性粒细胞炎症有关，但先前尚未在大型前瞻性成人UC队列中进行研究。由于这一观察结果的新奇，研究嗜酸性粒细胞趋化因子-1在结肠炎和结肠炎相关致癌作用的小鼠模型中的作用是这一提议的重点。沿着血清和组织嗜酸性粒细胞活化趋化因子-1的增加，与对照相比，UC患者中结肠组织嗜酸性粒细胞显著增加，并且嗜酸性粒细胞计数与组织嗜酸性粒细胞活化趋化因子-1水平相关。Eotaxin-1在葡聚糖硫酸钠（DSS）诱导的结肠炎中被我的合作者证明是增加的，并且我们现在第一次证明Eotaxin-1在以下方面被上调：1） 啮齿类柠檬酸杆菌诱导的结肠炎组织; 2）T细胞转移诱导的结肠炎组织; 3）在结肠炎相关致癌作用的氧化偶氮甲烷（AOM）-DSS模型中诱导的肿瘤;和4）用C.啮齿动物。然而，Eotaxin-1在小鼠幽门螺杆菌诱导的胃炎组织中没有增加，表明这不是一个非特异性的表达。 炎症的特定成分。假设：Eotaxin-1是结肠炎和结肠炎相关致癌作用的关键介质，通过影响巨噬细胞和上皮细胞。该项目的具体目标是：1。探讨嗜酸性粒细胞趋化因子-1在实验性结肠炎发病机制中的作用。我们将使用C。涉及免疫激活的结肠炎的啮齿动物感染模型和涉及免疫激活和上皮损伤的结肠炎的T细胞转移模型。我们将比较野生型（WT）和嗜酸性粒细胞趋化因子1-/-小鼠在C。啮齿动物模型以及嗜酸细胞活化趋化因子1 +/+ Rag 2-/-和嗜酸细胞活化趋化因子1-/-Rag 2-/-小鼠，在T细胞转移模型中有和没有过继转移CD 4 + CD 45 RBhi效应T细胞。在每种结肠炎模型中，将评估以下内容：临床参数、结肠和全身先天免疫应答（侧重于巨噬细胞表型和功能）以及上皮功能。2.确定嗜酸性粒细胞趋化因子-1在慢性结肠炎和结肠炎相关癌发生（CAC）中的调节作用。我们的初步数据首次显示，AOM-DSS模型中结肠炎相关肿瘤的嗜酸性粒细胞趋化因子-1水平增加。我们将在WT和eotaxin 1-/-小鼠中利用AOM-DSS模型来确定由eotaxin-1缺失引起的炎症反应的修饰是否可以降低CAC的风险。在慢性结肠炎（用多个DSS周期处理的小鼠）和结肠炎相关的肿瘤发生（用AOM处理的小鼠，然后用多个DSS周期处理）中，将评估以下内容：临床参数，包括肿瘤大小和多样性，结肠和全身先天免疫应答，侧重于巨噬细胞表型和功能，以及上皮功能，包括肿瘤和邻近的非肿瘤组织。这些研究将为Eotaxin-1在IBD和相关致癌作用中的作用提供新的机制见解。