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
基本信息
- 批准号:8510329
- 负责人:
- 金额:$ 5.7万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-04-01 至 2013-08-10
- 项目状态:已结题
- 来源:
- 关键词:Academic Medical CentersAffectAmericanAnimalsAnti-Tumor Necrosis Factor TherapyAsthmaAwardBiological AssayBiological MarkersChildChildhoodChimeric ProteinsChronicClinicalClinical TrialsColectomyColitisCrohn&aposs diseaseCytokine SignalingDataData AnalysesDevelopmentDigestive System DisordersDiseaseDoctor of PhilosophyEducational workshopEnvironmentEpithelialExhibitsFlow CytometryFundingFutureGastroenterologistGene ExpressionGenesGeneticGoalsHelicobacter pyloriHumanImmuneImmune responseImmunologistImmunologyInfiltrationInflammationInflammatoryInflammatory Bowel DiseasesInflammatory ResponseInflammatory disease of the intestineInterleukin 2 ReceptorInterleukin-13Interleukin-4Intestinal MucosaInvestigationK-Series Research Career ProgramsLaboratoriesLymphocyteLymphoid CellMaster of ScienceMediatingMedicalMentorsMentorshipMicroarray AnalysisModelingMonoclonal AntibodiesMorbidity - disease rateMucosal Immune ResponsesMucous MembraneMusOutcomeOxazolonePathogenesisPathway interactionsPatient CarePatientsPediatricsPhase II Clinical TrialsPhysiciansPositioning AttributeProductionProteinsPublishingRNARNA SequencesRefractoryResearchResearch PersonnelResearch ProposalsResearch TrainingRoleSTAT6 Transcription FactorScientistSeveritiesTNF geneTechniquesTherapeuticTimeTissuesTrainingTraining ProgramsTranscriptTranslational ResearchUlcerative ColitisUnited States National Institutes of HealthWild Type MouseWorkactivating transcription factoradaptive immunityattenuationcareercareer developmentcohortcytokineeffective therapyfollow-upgenome-widein vivokiller T celllaboratory facilitylarge bowel Crohn&aposs diseasemacrophagemeetingspatient oriented researchphase 2 studyprofessorprogramsprospectiveprotein expressionpublic health relevanceranpirnasereceptorresponseskills training
项目摘要
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(由申请人提供):这个职业发展奖的总体目标是提供一个全面的培训计划,为我准备一个独立资助的转化研究职业生涯,专注于小儿炎症性肠病(IBD)的免疫发病机制。我是一名儿科助理教授和董事会认证的儿科胃肠病学家,拥有以患者为导向的研究高级学位(临床研究科学硕士,MSCI)。我的近期目标是获得粘膜免疫学和功能遗传学方面的额外专业知识,同时继续研究Th 2炎症在儿科IBD中的作用。这个奖项将使我能够实现这一目标,
正式的研究生水平的课程,在关键技术,如流式细胞术和基因表达测定研讨会,并保护5年的指导研究。我的主要导师是医学博士基思威尔逊,他在IBD和H相关的转化粘膜免疫学方面有着良好的影响力研究记录。Pylori我的职业发展进一步受益于两位共同导师:Luc货车Kaer博士,国际公认的免疫学家,他在自然杀伤T细胞,适应性免疫和粘膜免疫学方面的专业知识,以及R。小斯托克斯皮布尔斯,医学博士,一位医学科学家,是Th 2炎症反应方面的专家。范德比尔特大学医学中心提供了一个丰富的研究和年轻研究人员的培训环境,通过临床和转化科学家发展办公室对所有指导的医生科学家进行集中监督。此外,我的实验室是嵌入在高生产率的NIH P30资助的范德比尔特消化疾病研究中心(DDRC),这将提供进一步的丰富,通过定期与其他DDRC研究人员,特邀演讲者的互动,并获得最先进的核心实验室设施。我的长期目标是成为一名独立资助的医生科学家,拥有独特的技能和培训,在一个大型转化IBD研究计划中连接人类和动物研究,这将影响这种疾病患者的护理。强有力的指导,额外的培训,以及本建议书中详细介绍的环境将使我最终实现这一目标。 这项研究计划扩展了我之前发表的关于Th 2炎症在小儿IBD中的作用的工作。溃疡性结肠炎(UC)和克罗恩病(CD)是影响150万美国人的肠道慢性炎症性疾病,其中5万是儿童。抗TNF治疗的出现标志着治疗的重大进展;然而,大量抗TNF治疗难治性UC患者表明其他炎症途径可驱动疾病。通常,CD中的肠粘膜与Th 1和Th 17炎症反应相关,而UC中的粘膜与非典型Th 2炎症相关。这种区别可能解释了许多UC患者的疾病难治性和儿科UC的20%结肠切除率。事实上,针对IL-13(一种拟议的致病性Th 2细胞因子)的单克隆抗体正在进行UC的2期试验。因此,重要的是要确定那些UC患者与上调的Th 2反应谁可能最受益于未来的Th 2导向治疗。因此,我们对初步的全基因组表达数据的分析表明,某些Th 2相关基因的表达将儿童UC与克罗恩氏结肠炎区分开来,并且IL-13受体2(IL- 33)和IL-33受体ST 2的转录物的高表达与5-氨基水杨酸(5-阿萨)治疗的难治性相关。IL-33是一种有效的Th 2细胞因子诱导剂,在UC中升高,但其在UC发病机制中的作用尚不清楚。我们的数据显示,在Th 2驱动的鼠恶唑酮结肠炎中,上皮细胞和巨噬细胞来源的IL- 33增加,并且STAT 6-/-小鼠表现出与IL-33表达降低相关的结肠炎严重程度降低。我们假设一部分儿童UC患者表现出Th 2粘膜免疫应答上调。此外,我们提出IL-33作为Th 2细胞因子产生的有效诱导剂,是小鼠Th 2介导的结肠炎的驱动因素,并与人类UC的疾病难治性相关。在目标1中,我们将确定是否有一部分儿童UC患者表现出Th 2炎症反应增强,以及这是否预示着对5-阿萨治疗的反应。我们的方法将是分析一组重点基因的粘膜表达,这些基因参与了CCFA儿科网络中一个大型儿科IBD病例的Th 2炎症,并提供了详细的前瞻性结局数据。来自范德比尔特IBD儿科患者的组织将用于验证蛋白质水平的结果。在目标2中,我们将确定IL-33在影响
通过在IL-33-/-小鼠、ST 2-/-小鼠和用可溶性ST 2融合蛋白处理的小鼠中诱导恶唑酮结肠炎,在鼠结肠炎中的先天性和适应性免疫机制。该项目将促进我们对Th 2炎症对IBD儿童治疗结果的影响的理解,并确定Th 2诱导细胞因子IL-33作为未来UC治疗靶点的潜力。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Michael J Rosen其他文献
PURE NATURAL ORIFICE TRANSLUMENAL ENDOSCOPIC SURGERY (NOTES) NEPHRECTOMY USING STANDARD LAPAROSCOPIC INSTRUMENTS IN THE PORCINE MODEL
- DOI:
10.1016/s0022-5347(08)60684-9 - 发表时间:
2008-04-01 - 期刊:
- 影响因子:
- 作者:
Justin P Isariyawongse;Michael F McGee;Edward E Cherullo;Michael J Rosen;Lee E Ponsky - 通讯作者:
Lee E Ponsky
Michael J Rosen的其他文献
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{{ truncateString('Michael J Rosen', 18)}}的其他基金
Epigenetic and functional determination of colon organoids as a patient-specific preclinical model of ulcerative colitis
结肠类器官作为溃疡性结肠炎患者特异性临床前模型的表观遗传学和功能测定
- 批准号:
10595943 - 财政年份:2020
- 资助金额:
$ 5.7万 - 项目类别:
Epigenetic and functional determination of colon organoids as a patient-specific preclinical model of ulcerative colitis
结肠类器官作为溃疡性结肠炎患者特异性临床前模型的表观遗传学和功能测定
- 批准号:
10240732 - 财政年份:2020
- 资助金额:
$ 5.7万 - 项目类别:
Epigenetic and functional determination of colon organoids as a patient-specific preclinical model of ulcerative colitis
结肠类器官作为溃疡性结肠炎患者特异性临床前模型的表观遗传学和功能测定
- 批准号:
10064167 - 财政年份:2020
- 资助金额:
$ 5.7万 - 项目类别:
Type 2 cytokines and innate lymphoid cells in pediatric ulcerative colitis
小儿溃疡性结肠炎中的 2 型细胞因子和先天淋巴细胞
- 批准号:
10596871 - 财政年份:2018
- 资助金额:
$ 5.7万 - 项目类别:
Impact of ST2 signaling and IBD risk variants on the intestinal epithelium
ST2 信号传导和 IBD 风险变异对肠上皮的影响
- 批准号:
9165525 - 财政年份:2016
- 资助金额:
$ 5.7万 - 项目类别:
Impact of ST2 signaling and IBD risk variants on the intestinal epithelium
ST2 信号传导和 IBD 风险变异对肠上皮的影响
- 批准号:
9298635 - 财政年份:2016
- 资助金额:
$ 5.7万 - 项目类别:
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:
8773156 - 财政年份:2013
- 资助金额:
$ 5.7万 - 项目类别:
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:
8629732 - 财政年份:2013
- 资助金额:
$ 5.7万 - 项目类别:
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 - 财政年份:2013
- 资助金额:
$ 5.7万 - 项目类别:
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:
9057025 - 财政年份:2013
- 资助金额:
$ 5.7万 - 项目类别:
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