Eosinophil:M2 Macrophage:CCL11 Axis in Experimental Colitis and Pediatric Cortico
实验性结肠炎和小儿皮质中的嗜酸性粒细胞:M2 巨噬细胞:CCL11 轴
基本信息
- 批准号:8638957
- 负责人:
- 金额:$ 33.28万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-04-01 至 2016-03-31
- 项目状态:已结题
- 来源:
- 关键词:17q12Adrenal Cortex HormonesAdultAffectAnti-Tumor Necrosis Factor TherapyBiological AssayBiological MarkersBiopsyBone MarrowCCL11 geneCalcium-Binding ProteinsChemotaxisChildChildhoodClinicalColectomyColitisColonCrohn&aposs diseaseDataDependencyDiagnosisDiseaseDisease remissionDisease susceptibilityEosinophiliaEuropeExposure toGenesGoalsGrowthHealedHistologicHistopathologyHumanITGAM geneIn VitroIncidenceInflammationInflammatoryInflammatory Bowel DiseasesIntestinesLeukocyte L1 Antigen ComplexLeukocytesLigandsLinkMaintenance TherapyMediatingMedicalMesalamineModelingMolecular WeightMovementMusNatural ImmunityNon-Steroidal Anti-Inflammatory AgentsNorth AmericaOperative Surgical ProceduresOrgan Culture TechniquesOutcome StudyPathway interactionsPatientsPopulationPredictive ValuePrognostic MarkerQuality of lifeRefractoryRefractory DiseaseRegulationRelapseRelative (related person)ResistanceRoleS100 ProteinsS100A8 geneS100A9 geneSeveritiesSodium Dextran SulfateSourceSteroidsTestingTherapeutic AgentsTimeTissuesUlcerative ColitisUp-Regulationaggressive therapybasecohortearly onseteosinophileosinophil peroxidaseeosinophilic inflammationfollow-uphealingimprovedindexingmacrophagemonocytep65prospectivereceptor for advanced glycation endproductsresearch studythiopurinetreatment response
项目摘要
DESCRIPTION (provided by applicant): Corticosteriods (CS) remains the mainstay of therapy for pediatric UC; however, 20% of patients fail to respond to CS therapy and require secondary-line therapies and escalation of medical management or colectomy4. In recent patient-based studies, we demonstrated that CCL11 levels correlated with tissue eosinophil numbers, which, in turn, correlated with the UC Histologic Index of Severity (UCHIS) in pediatric UC. In preliminary studies, we determined that high rectosigmoid eosinophil levels at the time of pediatric UC diagnosis is linked with reduced likelihood of achieving steroid-free remission (SFR). Notably, high eosinophil levels positively correlated with levels of CCL11 and a low molecular weight intracellular calcium binding protein called calprotectin. In experimental studies, we have identified a link between calprotectin, M¿-derived CCL11, and eosinophils in experimental colitis. Importantly, we show that colonic M¿s express the calprotectin receptor (RAGE); and calprotectin stimulates p65 activation and CCL11 expression in M¿s in vitro. The object of this application is to further understand the relative contribution of calprotectin to inflammatory M¿-derived CCL11 and eosinophilic inflammation in experimental colitis and pediatric UC and treatment responses. Our central hypothesis is that calprotectin-induced activation of M¿s regulates CCL11-dependent colonic eosinophilic inflammation in experimental colitis and pediatric UC and that this pathway drives refractory disease. We will test this hypothesis by examining the relationship between calprotectin, M¿s, CCL11, and eosinophils in pediatric UC at diagnosis and the relationship of this pathway to refractory disease. We will employ S100A9-/-, RAGE-/-, CCR2-/-, CCR2-/-/Il10-/- mice; use DSS- and NSAID-induced Il10-/- models of colitis; generate bone marrow-derived M¿-specific chimeric mice and perform eosinophil chemotaxis assays to define M¿-derived CCL11 in eosinophil recruitment and histopathology in experimental colitis and the sensitivity of this pathway to CS treatment. With respect to expected outcomes, the studies proposed in Aim I are expected to define the association between calprotecin, CCL11+ M¿s, and eosinophils in pediatric UC; the sensitivity of this pathway to CS; and the predictive value of CCL11 and eosinophils disease as an indicator of resistance to first-line therapies. Aim II is expected to delineate colonic eosinophilc inflammation and histopathology dependency on calprotectin/RAGE-induced M¿-derived CCL11 in experimental colitis. Aim III is expected to define the capacity of calprotectin/RAGE to induce M¿-derived CCL11 and eosinophil chemotaxis and sensitivity to CS-induced inhibition. Demonstration of calprotectin/M¿/CCL11/eosinophil axis involvement in resistance to first-line therapies in pediatric UC will have important clinical implications for both the usage of CCL11 and eosinophils as a prognostic indicator for resistance to first-line therapies at diagnosis and the possible usage of therapeutic agents targeting eosinophils and eosinophil regulatory molecules as an approach for improved treatment of pediatric UC and refractory UC.
描述(由申请人提供):皮质类固醇(CS)仍然是儿童UC的主要治疗方法;然而,20%的患者对CS治疗无效,需要二线治疗和药物管理升级或结肠切除术4。在最近的基于患者的研究中,我们证明了CCL 11水平与组织嗜酸性粒细胞数量相关,而嗜酸性粒细胞数量又与儿童UC的UC组织学严重程度指数(UCHIS)相关。在初步研究中,我们确定在儿童UC诊断时高直肠乙状结肠嗜酸性粒细胞水平与实现无类固醇缓解(SFR)的可能性降低有关。值得注意的是,高嗜酸性粒细胞水平与CCL 11和称为钙卫蛋白的低分子量细胞内钙结合蛋白的水平呈正相关。在实验研究中,我们已经确定了实验性结肠炎中钙卫蛋白、M?衍生的CCL 11和嗜酸性粒细胞之间的联系。重要的是,我们发现结肠M?s表达钙卫蛋白受体(calprotectin receptor,CaP);钙卫蛋白在体外刺激M?s中的p65激活和CCL 11表达。本申请的目的是进一步了解钙卫蛋白对实验性结肠炎和儿科UC中炎性M?衍生的CCL 11和嗜酸性粒细胞炎症的相对贡献以及治疗反应。我们的中心假设是,钙卫蛋白诱导的M?s激活调节实验性结肠炎和小儿UC中的CCL 11依赖性结肠嗜酸性粒细胞炎症,并且该途径驱动难治性疾病。我们将通过检查钙卫蛋白、M?s、CCL 11和嗜酸性粒细胞之间的关系以及该途径与难治性疾病的关系来检验这一假设。我们将使用S100 A9-/-、CCR 2-/-、CCR 2-/-/Il 10-/-小鼠;使用DSS和NSAID诱导的Il 10-/-结肠炎模型;产生骨髓来源的M <$特异性嵌合小鼠,并进行嗜酸性粒细胞趋化性测定,以确定实验性结肠炎中嗜酸性粒细胞募集和组织病理学中M <$来源的CCL 11以及该途径对CS治疗的敏感性。关于预期结局,目的I中提出的研究预期将确定儿童UC中钙卫蛋白、CCL 11 + M?s和嗜酸性粒细胞之间的相关性;该途径对CS的敏感性;以及CCL 11和嗜酸性粒细胞疾病作为一线治疗耐药指标的预测价值。目的II预期描述实验性结肠炎中结肠嗜酸性粒细胞炎症和组织病理学对钙卫蛋白/RAGE诱导的M?衍生的CCL 11的依赖性。目的III预期确定钙卫蛋白/钙卫蛋白诱导M?衍生的CCL 11和嗜酸性粒细胞趋化性的能力以及对CS诱导的抑制的敏感性。钙卫蛋白/M?的证明/CCL 11/嗜酸性粒细胞轴参与儿科UC一线治疗耐药将对使用CCL 11和嗜酸性粒细胞作为诊断时一线治疗耐药的预后指标以及可能使用靶向嗜酸性粒细胞和嗜酸性粒细胞调节分子的治疗药物作为改善儿科UC和难治性UC治疗的方法具有重要的临床意义。
项目成果
期刊论文数量(0)
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SIMON Patrick HOGAN其他文献
SIMON Patrick HOGAN的其他文献
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10752964 - 财政年份:2015
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Eosinophil:M2 Macrophage:CCL11 Axis in Experimental Colitis and Pediatric Cortico
实验性结肠炎和小儿皮质中的嗜酸性粒细胞:M2 巨噬细胞:CCL11 轴
- 批准号:
8297535 - 财政年份:2012
- 资助金额:
$ 33.28万 - 项目类别:
Eosinophil:M2 Macrophage:CCL11 Axis in Experimental Colitis and Pediatric Cortico
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- 批准号:
8451994 - 财政年份:2012
- 资助金额:
$ 33.28万 - 项目类别: