Probing the Mechanisms of Fibroblast-Extracellular Matrix Interactions to Assess Disease Severity in Allergic Eosinophilic Esophagitis
Probing the Mechanisms of Fibroblast-Extracellular Matrix Interactions to Assess Disease Severity in Allergic Eosinophilic Esophagitis
批准号:
10170261
负责人:
Seema S Aceves
金额:
$19.74万
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
已结题
起止时间:
2020-05-22 至 2023-04-30
关键词:
AllergicAllergic DiseaseAllergic inflammationAntigensAutologousAutomobile DrivingBiological AssayBiological ModelsBiopsyCD47 geneCell physiologyCellsCellular StructuresChildChildhoodChronicClinicalCollagenDataDeglutitionDiseaseEosinophiliaEosinophilic EsophagitisEsophagusExpert SystemsExtracellular MatrixFibroblastsFibrosisFoodFunctional disorderGrowthHealthcareHistologicHumanIn VitroInflammationKnowledgeMolecularMuscle functionOutcomePathologicPatient CarePatientsPatternPhenotypePlayPrevalenceProductionProtein AnalysisProteinsProteomeProteomicsRiskRoleScientistSeveritiesSeverity of illnessSmooth MuscleSmooth Muscle Actin Staining MethodSymptomsTGFB1 geneTestingThrombospondin 1TissuesVomitingangiogenesisbasecell motilitycohortcytokinedrug developmentdruggable targeteosinophilic inflammationexperimental studyfibrillogenesisimaging probein vivoindividualized medicineinhibitor/antagonistinsightlongitudinal databasemolecular markermotility disordermuscle hypertrophynew therapeutic targetnovelnovel strategiesnovel therapeuticspersonalized medicinephenotypic biomarkerpredictive markerprotein expressionreceptorscreeningsuccesstherapy resistanttranslational physiciantreatment response
中文摘要
项目摘要
嗜酸性食管炎(EoE)是一种由抗原引起的慢性过敏性疾病,可引起临床症状
呕吐,吞咽困难,儿童发育不良。由于慢性嗜酸性炎症,未经治疗的
或者治疗无效的EoE食道变得僵硬、狭窄和运动障碍,导致食物嵌塞。
组织重塑包括组织学上皮下纤维化、血管生成和平滑肌肥大
是EoE并发症的潜在机制。上皮下细胞外基质(ECM)在
在改变食道成纤维细胞和平滑肌功能中的不可或缺的作用。促纤维化因子可以成为
陷于ECM和基质刚性可以改变结构细胞的功能。然而,我们目前缺乏一种
了解EoE ECM中纤维化的主要分子驱动因素以及ECM之间的相互作用
成纤维细胞可以反映EoE的疾病严重程度或预测食道狭窄的风险。此外,还有
没有简单的方法来衡量对抗重塑化合物的治疗反应-这是患者护理和
药物开发。这些问题为最佳病人护理创造了巨大的知识差距。同时发炎
启动组织重塑,它既不是食道功能障碍的唯一传播因子,也不是最好的预测因素
病理性纤维化的标志物。在本应用中,我们建议使用原代人食道成纤维细胞
不同程度EoE患者与来自正常食道的ECM之间的相互作用
以及成纤维细胞,以破译驱动成纤维细胞功能变化的最相关分子。至
要做到这一点,我们将使用有针对性的蛋白质分析和无偏见的蛋白质组学方法。然后我们计划
使用我们的实验方法评估潜在的抗重塑化合物阻断细胞外基质的能力
诱导成纤维细胞功能改变,从而打造潜在的个性化抗逆转录病毒药物平台
纤维状化合物。我们将把我们的体外研究结果与体内蛋白质表达研究以及长期的
使用我们的表型良好的纵向EoE队列的术语疾病轨迹。我们假设这些研究
将确定改变EoE进程并作为新的治疗靶点的新的相关蛋白质
用于治疗疾病并发症。
英文摘要
Project Summary
Eosinophilic esophagitis (EoE) is a chronic, antigen driven allergic disease that causes clinical symptoms of
vomiting, trouble swallowing, and poor growth in children. Due to chronic eosinophilic inflammation, the untreated
or therapy unresponsive EoE esophagus becomes rigid, narrowed, and dysmotile, resulting in food impactions.
Tissue remodeling includes histologic subepithelial fibrosis, angiogenesis and smooth muscle hypertrophy and
is the underlying mechanism for EoE complications. The subepithelial extracellular matrix (ECM) plays an
integral role in changing esophageal fibroblast and smooth muscle function. Pro-fibrotic factors can become
trapped in the ECM and matrix rigidity can alter structural cell functions. However, we currently lack an
understanding of the main molecular drivers of fibrosis in the EoE ECM and if the interactions between the ECM
and fibroblasts can reflect disease severity or predict the risk of esophageal narrowing in EoE. Further, there are
no easy ways to gauge therapeutic response to anti-remodeling compounds—a hinderance for patient care and
drug development. These issues create significant knowledge gaps for optimal patient care. While inflammation
initiates tissue remodeling, it is neither the sole propagator of esophageal dysfunction nor the best predictive
marker of pathological fibrosis. In this application we propose to use primary human esophageal fibroblasts from
patients with varying severities of EoE and from normal esophagi to understand the interaction between the ECM
and fibroblasts in order to decipher the most relevant molecules driving changes in fibroblast function. To
accomplish this, we will use both targeted protein analysis and an unbiased proteomic approach. We then plan
to use our experimental approach to assess the ability of potential anti-remodeling compounds to block ECM
induced changes in fibroblast function, thereby creating a potential personalized medicine platform for anti-
fibrotic compounds. We will align our in vitro findings with in vivo protein expression studies and with the long-
term disease trajectory using our well phenotyped longitudinal EoE cohort. We hypothesize that these studies
will determine novel and relevant proteins that alter the course of EoE and function as new therapeutic targets
for disease complications.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
LIGHT/TNFSF14 in allergic esophagitis remodeling
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批准号:9883001
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项目类别:
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资助金额:$57.49万
-
财政年份:2018
-
负责人:Seema S Aceves
-
依托单位:
LIGHT/TNFSF14 in allergic esophagitis remodeling
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批准号:10115702
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项目类别:
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资助金额:$56.89万
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财政年份:2018
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负责人:Seema S Aceves
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依托单位:
Mentoring Patient Oriented Research in Allergic Eosinophilic Gastrointestinal Disorders
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批准号:10303048
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项目类别:
-
资助金额:$17.95万
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财政年份:2017
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负责人:Seema S Aceves
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依托单位:
Mentoring Patient Oriented Research in Allergic Eosinophilic Gastrointestinal Disorders
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批准号:10061531
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项目类别:
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资助金额:$17.95万
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财政年份:2017
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负责人:Seema S Aceves
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依托单位:
Contribution of rigid matrix to allergic eosinophilic esophagitis pathogenesis
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批准号:9288119
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项目类别:
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资助金额:$38.55万
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财政年份:2011
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负责人:Seema S Aceves
-
依托单位:
Mechanisms of tissue damage leading to chronic allergic eosinophilic esophagitis
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批准号:8290402
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项目类别:
-
资助金额:$38.75万
-
财政年份:2011
-
负责人:Seema S Aceves
-
依托单位:
Mechanisms of tissue damage leading to chronic allergic eosinophilic esophagitis
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批准号:8676644
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项目类别:
-
资助金额:$38.75万
-
财政年份:2011
-
负责人:Seema S Aceves
-
依托单位:
Mechanisms of tissue damage leading to chronic allergic eosinophilic esophagitis
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批准号:8476199
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项目类别:
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资助金额:$36.43万
-
财政年份:2011
-
负责人:Seema S Aceves
-
依托单位:
Contribution of rigid matrix to allergic eosinophilic esophagitis pathogenesis
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批准号:9109276
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项目类别:
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资助金额:$39.93万
-
财政年份:2011
-
负责人:Seema S Aceves
-
依托单位:
Contribution of rigid matrix to allergic eosinophilic esophagitis pathogenesis
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批准号:10794513
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项目类别:
-
资助金额:$19.75万
-
财政年份:2011
-
负责人:Seema S Aceves
-
依托单位:
Mechanisms of tissue damage leading to chronic allergic eosinophilic esophagitis
-
批准号:8025819
-
项目类别:
-
资助金额:$38.63万
-
财政年份:2011
-
负责人:Seema S Aceves
-
依托单位:
Pilot/Demonstration Cimical Research Projects Program
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批准号:8911244
-
项目类别:
-
资助金额:$16.67万
-
财政年份:--
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负责人:Seema S Aceves
-
依托单位:
Pilot/Demonstration Cimical Research Projects Program
-
批准号:8894250
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项目类别:
-
资助金额:$17.13万
-
财政年份:--
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负责人:Seema S Aceves
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依托单位:
海外基金