Contribution of rigid matrix to allergic eosinophilic esophagitis pathogenesis
刚性基质对过敏性嗜酸粒细胞性食管炎发病机制的贡献
基本信息
- 批准号:9288119
- 负责人:
- 金额:$ 38.55万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-07-01 至 2021-06-30
- 项目状态:已结题
- 来源:
- 关键词:AdultAllergicAllergic DiseaseAnti-Inflammatory AgentsAnti-inflammatoryAtomic Force MicroscopyAutomobile DrivingBiological ModelsBiologyBiomedical EngineeringBiopsyCCL26 geneCalcium ChannelCell physiologyCellsCellular biologyChildChildhoodChronicDataDeglutition DisordersDiagnosisDiseaseEndoscopyEosinophil Chemotactic FactorsEosinophilic EsophagitisEpithelialEpithelial Cell ProliferationEpithelial CellsEsophagealEsophageal mucous membraneEsophagusEsophagus motilityExtracellular MatrixExtracellular Matrix ProteinsFeedbackFibroblastsFibrosisFoodFoundationsFunctional disorderGene ExpressionGlucocorticoidsGrowthHealthcareHumanHypertrophyInflammationInflammatoryLifeMeasuresMediatingModelingMuscleMuscle ContractionMuscle functionMyofibroblastNatureOrganoidsPainPathogenesisPathogenicityPathway interactionsPhenotypePhysiologyPlasminogen Activator Inhibitor 1PopulationPrevalenceProductionProteinsQuality of lifeResearch PersonnelRoleSarcoplasmic ReticulumSeveritiesSilicone GelsSiliconesSmooth MuscleSmooth Muscle MyocytesTGFB1 geneTechniquesTechnologyTestingTissuesTractionTransgenic OrganismsTranslationscell motilityclinical carecostdesignfood antigengene functiongenetic regulatory proteinimaging probeimprovedinnovationmechanotransductionmolecular markermuscle hypertrophynovelphospholambanprotein expressionpublic health relevanceresponse
项目摘要
DESCRIPTION (provided by applicant): Eosinophilic esophagitis (EoE) is a chronic food antigen driven allergic disease of increasing prevalence (5.6/10,000) that requires endoscopy with biopsy for its diagnosis and management and creates a large healthcare burden with an estimated annual cost of up to $1 billion. Complications are caused by tissue remodeling that includes fibrosis and smooth muscle hypertrophy leading to a rigid, poorly motile, narrowed esophagus with food impactions and strictures. Children have pain, poor growth, dysphagia and persistent disease, underscoring a pressing need to understand the mechanisms of disease complications to effectively treat EoE, decrease the healthcare burden, and improve quality of life. We have shown that tissue remodeling begins early in childhood, responds variably to anti-inflammatory therapy, and that transforming growth factor beta-1 (TGFβ1) is integral to pediatric EoE. TGFβ1induces smooth muscle contraction via the calcium channel regulatory protein, phospholamban (PLN) and recently we have found that it induces epithelial expression of the pro-fibrotic factor plasminogen activator inhibitor-1 (PAI-1). The current disease paradigm is that
inflammation is the singular trigger for remodeling. However, our novel preliminary data support the paradigm shifting central hypothesis that a rigid matrix drives structural cell dysfunction to promote EoE remodeling by inducing smooth muscle hypertrophy, fibroblast production of extracellular matrix proteins, and epithelial proliferation. We propose 3 independent specific aims to: 1) dissect the role of PLN in rigid matrix-induced smooth muscle hypertrophy and contraction, 2) understand the effects of rigid matrix on EoE and normal fibroblast gene expression and delineate whether EoE matrix is sufficient to alter normal fibroblast function, and 3) to simultaneously measure pediatric esophageal rigidity and motility using a new application of endoscopic functional luminal imaging probe technology, to delineate if epithelial cell response to TGFβ1is increased by rigid matrix, and to understand if epithelial PAI-1 serves as a marker of esophageal function. In order to test these hypotheses we will utilize novel human model systems including precisely bioengineered silicone substrates with primary cells and new functional platforms including smooth muscle co-cultured esophageal organoids, ex vivo intact human esophageal mucosal strips and muscle bundles as well as transgenic cells. We have assembled a strong and unique team of investigators with expertise in translational EoE, cell biology, physiology, and esophageal motility and combined this with our large well-phenotyped EoE pediatric population. These studies are innovative in concept and design and will help to dissect the fundamental biology of the novel and central concept that a rigid matrix contributes to EoE pathogenesis.
描述(由申请人提供):嗜酸性食管炎(EoE)是一种慢性食物抗原驱动的过敏性疾病,患病率不断增加(5.6/10,000),需要内镜检查和活检进行诊断和管理,并造成巨大的医疗负担,估计每年的费用高达10亿美元。并发症是由组织重塑引起的,包括纤维化和平滑肌肥大,导致僵硬、运动不良、狭窄的食管,伴有食物嵌塞和狭窄。儿童有疼痛,生长不良,吞咽困难和持续性疾病,强调迫切需要了解疾病并发症的机制,以有效治疗EoE,减轻医疗负担,提高生活质量。我们已经证明,组织重塑始于儿童早期,对抗炎治疗反应迅速,转化生长因子β 1(TGFβ1)是儿童EoE不可或缺的一部分。TGFβ 1通过钙通道调节蛋白受磷蛋白(phospholamban,PLN)诱导平滑肌收缩,近年来发现TGFβ 1可诱导纤维化因子纤溶酶原激活物抑制剂-1(plasminogen activator inhibitor-1,派-1)的表达。目前的疾病模式是,
炎症是重塑的唯一触发因素。然而,我们的新的初步数据支持范式转变的中心假设,即刚性基质驱动结构细胞功能障碍,以促进EoE重塑诱导平滑肌肥大,成纤维细胞产生的细胞外基质蛋白,上皮细胞增殖。我们提出了三个独立的具体目标:1)剖析PLN在刚性基质诱导的平滑肌肥大和收缩中的作用,2)了解刚性基质对Eoe和正常成纤维细胞基因表达的影响,并阐明Eoe基质是否足以改变正常成纤维细胞功能,和3)使用内窥镜功能性管腔成像探针技术的新应用同时测量小儿食管刚性和运动性,目的:探讨刚性基质是否增加了食管上皮细胞对TGFβ 1的反应,以及上皮派-1是否可作为食管功能的标志物。为了检验这些假设,我们将利用新型人体模型系统,包括具有原代细胞的精确生物工程化硅胶基质和新的功能平台,包括平滑肌共培养的食管类器官、离体完整的人食管粘膜条和肌束以及转基因细胞。我们已经组建了一支强大而独特的研究团队,他们在翻译EoE、细胞生物学、生理学和食管动力学方面具有专业知识,并将其与我们庞大的表型良好的EoE儿科人群相结合。这些研究在概念和设计上是创新的,将有助于剖析刚性基质有助于EoE发病机制这一新的核心概念的基本生物学。
项目成果
期刊论文数量(0)
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Seema S Aceves其他文献
Seema S Aceves的其他文献
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{{ truncateString('Seema S Aceves', 18)}}的其他基金
Probing the Mechanisms of Fibroblast-Extracellular Matrix Interactions to Assess Disease Severity in Allergic Eosinophilic Esophagitis
探讨成纤维细胞-细胞外基质相互作用的机制以评估过敏性嗜酸性食管炎的疾病严重程度
- 批准号:
10170261 - 财政年份:2020
- 资助金额:
$ 38.55万 - 项目类别:
LIGHT/TNFSF14 in allergic esophagitis remodeling
LIGHT/TNFSF14 在过敏性食管炎重塑中的作用
- 批准号:
9883001 - 财政年份:2018
- 资助金额:
$ 38.55万 - 项目类别:
LIGHT/TNFSF14 in allergic esophagitis remodeling
LIGHT/TNFSF14 在过敏性食管炎重塑中的作用
- 批准号:
10115702 - 财政年份:2018
- 资助金额:
$ 38.55万 - 项目类别:
Mentoring Patient Oriented Research in Allergic Eosinophilic Gastrointestinal Disorders
指导过敏性嗜酸性粒细胞胃肠道疾病的以患者为导向的研究
- 批准号:
10303048 - 财政年份:2017
- 资助金额:
$ 38.55万 - 项目类别:
Mentoring Patient Oriented Research in Allergic Eosinophilic Gastrointestinal Disorders
指导过敏性嗜酸性粒细胞胃肠道疾病的以患者为导向的研究
- 批准号:
10061531 - 财政年份:2017
- 资助金额:
$ 38.55万 - 项目类别:
Mechanisms of tissue damage leading to chronic allergic eosinophilic esophagitis
导致慢性过敏性嗜酸性粒细胞性食管炎的组织损伤机制
- 批准号:
8290402 - 财政年份:2011
- 资助金额:
$ 38.55万 - 项目类别:
Mechanisms of tissue damage leading to chronic allergic eosinophilic esophagitis
导致慢性过敏性嗜酸性粒细胞性食管炎的组织损伤机制
- 批准号:
8676644 - 财政年份:2011
- 资助金额:
$ 38.55万 - 项目类别:
Mechanisms of tissue damage leading to chronic allergic eosinophilic esophagitis
导致慢性过敏性嗜酸性粒细胞性食管炎的组织损伤机制
- 批准号:
8476199 - 财政年份:2011
- 资助金额:
$ 38.55万 - 项目类别:
Contribution of rigid matrix to allergic eosinophilic esophagitis pathogenesis
刚性基质对过敏性嗜酸粒细胞性食管炎发病机制的贡献
- 批准号:
9109276 - 财政年份:2011
- 资助金额:
$ 38.55万 - 项目类别:
Contribution of rigid matrix to allergic eosinophilic esophagitis pathogenesis
刚性基质对过敏性嗜酸粒细胞性食管炎发病机制的贡献
- 批准号:
10794513 - 财政年份:2011
- 资助金额:
$ 38.55万 - 项目类别:
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