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:10794513
- 负责人:
- 金额:$ 19.75万
- 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 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:5&apos-NucleotidaseAdenosineAdultAffectAllergicAllergic DiseaseAnti-Inflammatory AgentsAntigensAutomobile DrivingBiological AssayBiopsyBlocking AntibodiesCD14 geneCellsCellular Indexing of Transcriptomes and Epitopes by SequencingChildChondrocytesChronicChronic DiseaseClinicalClinical TrialsCollagenComplicationCountryDataData SetDeglutition DisordersDiseaseDisease remissionENG geneEatingEndoscopyEosinophilic EsophagitisEsophageal StenosisEsophagusExtracellular MatrixFailure to ThriveFibroblastsFibrosisFlow CytometryFoodFoundationsFunctional disorderGene ExpressionGenerationsGenesGenetic TranscriptionGoalsHealth Care CostsHumanImmunologic ReceptorsIndividualInfiltrationInflammationInflammatoryInterferon Type IInterferonsKnowledgeLegal patentLigandsLongitudinal cohortMechanicsMicroinjectionsMucous MembraneMyofibroblastNatural HistoryNucleotidasesOrganOrganoidsPathogenesisPathogenicityPatientsPatternPersonsPhenotypePhysiologicalPrevalenceProteomeProteomicsRNA SequencesRecurrenceRoleSeveritiesSeverity of illnessSignal TransductionSourceSurfaceTechnologyTestingTherapeutic Clinical TrialTherapeutic antibodiesTimeTissue ProcurementsTissuesTranscriptTransforming Growth Factor betaTransgenesVomitingcalcificationcell motilitycohortcomputational platformcostextracellularin vivomultidisciplinarynovelpatient populationprotein expressionresponsesingle-cell RNA sequencingtranscriptome sequencingtransgene expressiontranslational impactwound healing
项目摘要
Project Abstract
Eosinophilic esophagitis (EoE) is a chronic antigen driven type 2 (T2) inflammatory disease affecting up to 1 in
1000 people. EoE requires repeated endoscopy, costing 1.4 billion dollars annually. Chronic untreated or therapy
unresponsive EoE leads to progressive esophageal dysfunction due to tissue remodeling and fibrosis.
Remodeling causes esophageal rigidity, strictures, clinical dysphagia, food impactions, and failure to thrive. Up
to 50% of patients can be non-responsive to standard therapy. Our knowledge gap in treating or reversing fibrosis
leaves a dearth of therapies for patients with the greatest need. This situation creates a pressing requirement to
understand the mechanisms and cells driving tissue remodeling. Over the last 2 cycles of this R01, we have
demonstrated EoE remodeling mechanisms including the effects of TGFβ1 and rigid matrix on esophageal
structural cells. We have delineated the EoE inflammatory and remodeling natural history in children. We
demonstrated that the EoE fibroblast-derived extracellular matrix (ECM) proteome is unique and sufficient to
create a pro-fibrotic myofibroblast phenotype in normal esophageal fibroblasts. These data implicate the EoE
fibroblast, itself, as distinct from normal. Single cell RNA sequencing (scRNA-seq) analysis of 3 independent
datasets consistently demonstrate 3 transcriptional fibroblast phenotypes that we term secretory (s-), myo-, and
inflammatory (i-) fibroblasts. Our proteomic, RNA sequencing, and functional studies demonstrate that the EoE
fibroblast has increased type I interferon (IFN-I) response, is more motile, expresses pro-inflammatory CD14,
and forms rigid cells. scRNA-seq shows that i-fibroblasts carry an IFN-I response gene pattern. S-fibroblasts are
predicted to be collagen producing and pro-inflammatory and be the source for i- and myo-fibroblasts. CD73 is
a 5’-nucleotidase that is decreased on EoE s-fibroblasts. CD73 generates anti-inflammatory adenosine and
protects from tissue calcification. We propose the central hypothesis that combined decreases in CD73 and
increases in CD14 create pathogenic EoE fibroblasts that are poised for rigidity, inflammation, and tissue
infiltration. In Aim 1, we will decipher the most pathogenic functions in EoE fibroblasts. We will experimentally
investigate the generation of i- and m-fibroblasts from early s-fibroblasts. Using our >15 year longitudinal EoE
patient cohort and objective definitions of severity, we will understand which fibroblast phenotypes are retained
and lost in severe and mild longitudinal EoE. In Aim 2, we increase and decrease CD73 and CD14 expression
and function using transgenes, activating ligands, and a blocking antibody in therapeutic clinical trials. We will
understand if loss of fibroblast CD73 aligns with severe and non-remission EoE and if retention of fibroblasts
with CD14 are detrimental to EoE course. We uniquely involve a multidisciplinary team, cutting edge technology,
and novel computational platforms. For the first time, we will begin to fill our knowledge gap in EoE fibroblast
dysfunction which is imperative for controlling esophageal remodeling in children and adults.
项目摘要
嗜酸性食管炎(EoE)是一种慢性抗原驱动的2型(T2)炎性疾病,
一千人。EoE需要反复进行内窥镜检查,每年花费14亿美元。慢性未经治疗或治疗
无反应的EoE由于组织重塑和纤维化而导致进行性食管功能障碍。
重塑导致食管僵硬、狭窄、临床吞咽困难、食物嵌塞和发育不良。起来
到50%的患者对标准治疗无反应。我们在治疗或逆转纤维化方面的知识差距
给最需要的病人留下了治疗方法的匮乏。这种情况迫切需要
了解驱动组织重塑的机制和细胞。在本R01的最后2个周期中,我们有
证实了EoE重塑机制,包括TGF β 1和刚性基质对食管上皮细胞的影响。
结构细胞我们描述了儿童EoE炎症和重塑的自然史。我们
证明EoE成纤维细胞衍生的细胞外基质(ECM)蛋白质组是独特的,足以
在正常食管成纤维细胞中产生促纤维化肌成纤维细胞表型。这些数据表明,
成纤维细胞,本身,不同于正常。3个独立的单细胞RNA测序(scRNA-seq)分析
数据集一致地证明了3种转录成纤维细胞表型,我们称之为分泌型(S-)、肌型和
炎性(i-)成纤维细胞。我们的蛋白质组学,RNA测序和功能研究表明,EoE
成纤维细胞具有增加的I型干扰素(IFN-I)应答,更活跃,表达促炎性CD 14,
并形成刚性细胞。scRNA-seq显示i-成纤维细胞携带IFN-I应答基因模式。S-成纤维细胞是
预测为产生胶原蛋白和促炎性的,并且是I-和肌-成纤维细胞的来源。CD73是
一种在EoE s-成纤维细胞上减少的5'-核苷酸酶。CD73产生抗炎腺苷,
防止组织钙化。我们提出了一个中心假设,即CD73和
CD14的增加产生了致病性EoE成纤维细胞,这些成纤维细胞准备好了僵硬、炎症和组织损伤。
浸润在目标1中,我们将破译EoE成纤维细胞中最致病的功能。我们将实验性地
研究从早期S-成纤维细胞产生I-和M-成纤维细胞。使用我们的> 15年纵向EoE
患者队列和严重程度的客观定义,我们将了解哪些成纤维细胞表型被保留
在重度和轻度纵向EoE中丢失。在目标2中,我们增加和减少CD73和CD14的表达,
并在治疗性临床试验中使用转基因、活化配体和阻断抗体发挥功能。我们将
了解成纤维细胞CD73的丢失是否与重度和非缓解期EoE一致,以及成纤维细胞CD73的保留是否与重度和非缓解期EoE一致。
CD14对EoE病程不利。我们独特地涉及多学科团队,尖端技术,
和新颖的计算平台。我们将开始填补我们在EoE成纤维细胞方面的知识空白
这是控制儿童和成人食管重塑所必需的功能障碍。
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(1)
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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:
$ 19.75万 - 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:
$ 19.75万 - 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:
$ 19.75万 - 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:
$ 19.75万 - 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:
$ 19.75万 - 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:
9288119 - 财政年份:2011
- 资助金额:
$ 19.75万 - 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:
$ 19.75万 - 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:
$ 19.75万 - 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:
$ 19.75万 - 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:
$ 19.75万 - 项目类别:
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