Th2 Cytokines and Signaling in Pediatric Inflammatory Bowel Disease

儿科炎症性肠病中的 Th2 细胞因子和信号传导

• 批准号: 8850851
• 负责人: Michael J Rosen
• 金额: $ 17.94万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8850851
• 关键词: Academic Medical Centers; Affect; American; Animals; Anti-Tumor Necrosis Factor Therapy; Asthma; Award; Biological Markers; Child; Childhood; Chimeric Proteins; Chronic; Clinical; Colectomy; Colitis; Crohn' s disease; Cytokine Signaling; Data; Data Analyses; Development; Digestive System Disorders; Disease; Doctor of Philosophy; Educational workshop; Environment; Epithelial; Exhibits; Flow Cytometry; Funding; Future; Gastroenterologist; Gene Expression; Gene Expression Profiling; Genes; Genetic; Goals; Health; Helicobacter pylori; Human; Immune; Immune response; Immunologist; Immunology; Infiltration; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Inflammatory disease of the intestine; Interleukin 2 Receptor; Interleukin-13; Interleukin-4; Intestinal Mucosa; Investigation; K-Series Research Career Programs; Laboratories; Lymphocyte; Lymphoid Cell; Master of Science; Mediating; Medical; Mentors; Mentorship; Microarray Analysis; Modeling; Monoclonal Antibodies; Morbidity - disease rate; Mucosal Immune Responses; Mucous Membrane; Mus; Outcome; Oxazolone; Pathogenesis; Pathway interactions; Patient Care; Patients; Pediatrics; Phase II Clinical Trials; Physicians; Positioning Attribute; Production; Proteins; Publishing; RNA; RNA Sequences; Refractory; Research; Research Personnel; Research Proposals; Research Training; Role; STAT6 Transcription Factor; Scientist; Severities; TNF gene; Techniques; Therapeutic; Time; Tissues; Training; Training Programs; Transcript; Translational Research; Ulcerative Colitis; United States National Institutes of Health; Wild Type Mouse; Work; activating transcription factor; adaptive immunity; attenuation; career; career development; clinical investigation; cohort; cytokine; effective therapy; follow-up; genome-wide; in vivo; killer T cell; laboratory facility; large bowel Crohn' s disease; macrophage; meetings; patient oriented research; phase 2 study; professor; programs; prospective; protein expression; ranpirnase; receptor; response; skills training; transcriptome sequencing

DESCRIPTION (provided by applicant): The overarching goal of this career development award is to provide a comprehensive training program to prepare me for an independently funded translational research career focused on the immunopathogenesis of pediatric inflammatory bowel disease (IBD). I am an Assistant Professor of Pediatrics and board-certified pediatric gastroenterologist with an advanced degree in patient-oriented research (Masters of Science in Clinical Investigation, MSCI). My near-term goal is to acquire additional expertise in mucosal immunology and functional genetics while continuing a productive line of investigation into the role of Th2 inflammation in pediatric IBD. This award will allow me to meet this goal with formal graduate-level coursework, workshops in key techniques such as flow-cytometry and gene expression assays, and protection for 5 years of mentored research. My primary mentor is Keith Wilson, MD, who has a well-established track record of high impact research in translational mucosal immunology related to IBD and H. Pylori. My career development is further benefited by two co-mentors; Luc Van Kaer, PhD, an immunologist internationally recognized for his expertise in natural killer T cells, adaptive immunity, and mucosal immunology, and R. Stokes Peebles, Jr., MD, a physician-scientist who is an expert on Th2 inflammatory responses. Vanderbilt University Medical Center provides a rich environment for research and the training of young investigators with centralized oversight of all mentored physician scientists through the Office of Clinical & Translational Scientist Development. Furthermore, my laboratory is embedded within the highly productive NIH P30 funded Vanderbilt Digestive Disease Research Center (DDRC), which will provide further enrichment though regular interaction with other DDRC investigators, invited speakers, and access to state-of-the-art core laboratory facilities. My long-term goal is to become an independently-funded physician-scientist with the unique skills and training to bridge both human and animal studies within a large translational IBD research program that will impact the care of patients with this disease. The strong mentorship, additional training, and environment detailed in this proposal will position me to ultimately reach this objective. The research proposal extends my prior published work on the role of Th2 inflammation in pediatric IBD. Ulcerative colitis (UC) and Crohn's Disease (CD), are chronic inflammatory disorders of the intestine that affect 1.5 million Americans, 50,000 of whom are children. The advent of anti-TNF therapy marked a major advance in treatment; however, the substantial number of UC patients refractory to anti-TNF therapy suggests that other inflammatory pathways can drive the disease. Classically, the intestinal mucosa in CD has been associated with Th1 and Th17 inflammatory responses, while the mucosa in UC is associated with atypical Th2 inflammation. This distinction may explain the disease refractoriness of many UC patients and the 20% colectomy rate for pediatric UC. In fact, monoclonal antibodies against IL-13, a proposed pathogenic Th2 cytokine, are in phase 2 trials for UC. Therefore, it will be important to identify those UC patients with upregulated Th2 responses who may most benefit from future Th2-directed therapy. Accordingly, our analysis of preliminary genome-wide expression data suggests that expression of certain Th2-related genes distinguishes pediatric UC from Crohn's colitis, and that high expression of transcripts for IL-13 receptor ¿2, IL- 33, and the IL-33 receptor, ST2, is associated with refractoriness to 5-aminosalycilate (5-ASA) therapy. IL-33 is a potent inducer of Th2 cytokines and is increased in UC, but its role in UC pathogenesis is not clear. Our data show that in the Th2-driven murine oxazolone colitis, there is increased epithelial- and macrophage-derived IL- 33, and that STAT6-/- mice exhibit decreased colitis severity correlated to reduced IL-33 expression. We hypothesize that a subset of pediatric UC patients exhibits an upregulated Th2 mucosal immune response. Furthermore, we propose that IL-33, as a potent inducer of Th2 cytokine production, is a driver of murine Th2- mediated colitis and associated with disease refractoriness in human UC. In Aim 1, we will determine whether a subset of pediatric UC patients exhibit heightened Th2 inflammatory responses, and whether this predicts response to 5-ASA therapy. Our approach will be to analyze mucosal expression of a focused set of genes involved in Th2 inflammation in a large pediatric IBD inception from the CCFA Pediatric Network with detailed prospective outcomes data. Tissues from Vanderbilt pediatric IBD patients will be used to validate findings at the protein level. In Aim2, we will determine the role of IL-33 in influencing innate and adaptive immune mechanisms in murine colitis by inducing oxazolone colitis in IL-33-/- mice, ST2-/- mice, and mice treated with soluble ST2 fusion protein. This project will advance our understanding of the influence of Th2 inflammation on therapeutic outcome in children with IBD and determine the potential of the Th2-inducing cytokine IL-33 as a target for future UC therapy.

描述（由适用提供）：这一职业发展奖的总体目标是提供一项全面的培训计划，使我为我的独立资助的翻译研究职业做好准备，专注于儿科炎症性肠病（IBD）的免疫发病生成。我是儿科和经过董事会认证的小儿胃肠病医生的助理教授，并获得了以患者为导向的研究学位（临床研究硕士学位，MSCI）。我的近期目标是获得粘膜免疫学和功能遗传学方面的更多专业知识，同时继续对Th2注射在小儿IBD中的作用进行生产性投资。这个奖项将使我能够实现这个目标 正式的研究生级课程，关键技术的讲习班，例如流程仪和基因表达测定法，以及为5年的指导研究提供保护。我的主要导师是医学博士基思·威尔逊（Keith Wilson），他在与IBD和H. Pylori有关的转化性粘膜免疫学方面具有良好的高影响研究记录。我的职业发展得到了两位联合委员的进一步受益。卢克·范·凯尔（Luc Van Kaer）博士是一名免疫学家，以国际自然杀手T细胞，适应性免疫学和粘膜免疫学专业知识以及R. Stokes Peebles，Jr.，MD，MD，是TH2炎症反应的专家。范德比尔特大学医学中心为研究提供了丰富的环境，并通过临床和转化科学家开发办公室对所有受过体育科学家进行集中监督的年轻研究人员进行了培训。此外，我的实验室嵌入了高产的NIH P30资助的Vanderbilt消化疾病研究中心（DDRC）中，该研究中心（DDRC）将通过与其他DDRC研究人员进行定期互动，邀请扬声器，并获得最先进的核心实验室设施，从而提供进一步的富集。我的长期目标是成为一名独立资助的身体科学家，并具有独特的技能和培训，以弥合大型翻译的IBD研究计划中的人类和动物研究，这将影响这种疾病患者的护理。该提案中详细介绍的强烈心态，额外的培训和环境将使我最终达到这一目标。该研究提案扩展了我先前发表的有关Th2感染在小儿IBD中的作用的工作。溃疡性结肠炎（UC）和克罗恩病（CD）是肠道的慢性炎症性疾病，影响了150万美国人，其中50,000名是儿童。抗TNF疗法的进步标志着治疗方面的重大进展。但是，对抗TNF疗法难治性的大量UC患者表明，其他炎症途径可以推动疾病。从经典上讲，CD中的肠粘膜与Th1和Th17炎症反应有关，而UC中的粘膜与非典型TH2炎症有关。该疾病可能解释了许多UC患者的疾病疾病，小儿UC的收集率为20％。实际上，针对IL-13的单克隆抗体（提出的一种致病性TH2细胞因子）正在对UC的2阶段试验中。因此，重要的是要确定那些具有更新的TH2反应的UC患者可能会从未来的TH2定向治疗中受益。根据我们对初步基因组表达数据的分析，表明，克罗恩的结肠炎的某些Th2相关基因独特的小儿UC的表达，以及IL-13受体€2，iL-33的转录物高表达，IL-33受体ST2和IL-33受体ST2，以及与5-氨基菌的屈光度相关（5-- amiNosAsyAsa）。 IL-33是Th2细胞因子的潜在诱导剂，在UC中增加，但其在UC发病机理中的作用尚不清楚。我们的数据表明，在Th2驱动的鼠恶唑酮结肠炎中，上皮和巨噬细胞衍生的IL-33增加，而STAT6 - / - 小鼠暴露于与IL-33表达降低相关的结肠炎严重程度。我们假设一部分儿科UC患者表现出更新的Th2粘膜免疫响应。此外，我们建议IL-33作为Th2细胞因子产生的潜在诱导剂，是鼠Th2-介导的结肠炎的驱动力，与人类UC中的疾病耐耐磨性有关。在AIM 1中，我们将确定一部分小儿UC患者是否表现出TH2炎症反应的增强，以及这种预测对5-ASA治疗的反应。我们的方法是分析来自CCFA儿科网络中具有详细的预期结果数据的大型儿科IBD启动中涉及Th2炎症基因的粘膜表达。范德比尔特小儿IBD患者的组织将用于验证蛋白质水平的发现。在AIM2中，我们将确定IL-33影响的作用 通过在IL-33 - / - 小鼠，ST2 - / - 小鼠以及用固体ST2融合蛋白治疗的小鼠中，通过诱导羟唑酮结肠炎和鼠结肠炎中的先天和适应性免疫机制。该项目将提高我们对IBD儿童Th2注射对热结局的影响的理解，并确定Th2诱导的细胞因子IL-33的潜力，作为未来UC治疗的靶标。