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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
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
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

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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.
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LIGHT/TNFSF14 in allergic esophagitis remodeling
LIGHT/TNFSF14 in allergic esophagitis remodeling
Mentoring Patient Oriented Research in Allergic Eosinophilic Gastrointestinal Disorders
Mentoring Patient Oriented Research in Allergic Eosinophilic Gastrointestinal Disorders
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