Tissue remodeling in Eosinophilic Esophagitis: Discovery of novel pathways

嗜酸性食管炎的组织重塑：新途径的发现

• 批准号: 10214610
• 负责人: CALIES D Menard-Katcher
• 金额: $ 11.66万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-10 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10214610
• 关键词: Address; Adolescent; Adult; Affect; Allergens; Appearance; Binding; Biological Models; Biopsy; Cell Line; Child; Childhood; Chronic; Clinical; Collaborations; Critical Pathways; Data; Databases; Deglutition; Deglutition Disorders; Development; Diet therapy; Disease; Disease Marker; Disease Progression; Disease remission; Drug Targeting; Eosinophilic Esophagitis; Epithelial; Esophageal Diseases; Esophageal Stenosis; Esophageal mucous membrane; Esophagus; Evaluation; Extracellular Matrix; Extracellular Matrix Proteins; FDA approved; Family; Fibroblasts; Fibrosis; Food; Future; Gene Expression; Gene Expression Regulation; Genes; Goals; Histology; Human; In Vitro; Inflammation; Inflammatory; Institutional Review Boards; Investigation; K-Series Research Career Programs; Kidney; Knowledge; Lung; Mediating; Mentored Patient-Oriented Research Career Development Award; Methods; Molecular; Multiomic Data; NF-kappa B; Outcome; Participant; Pathogenesis; Pathogenicity; Pathologic; Pathway Analysis; Pathway interactions; Patients; Phenotype; Phosphorylation; Post-Translational Protein Processing; Proteins; Proteome; Proteomics; Regulation; Research; Risk; Role; Sampling; Signal Pathway; Signal Transduction; Skin; Smad Proteins; Steroids; Symptoms; Technology; Tissues; Transforming Growth Factor beta; Transgenic Mice; Transgenic Organisms; attenuation; base; biobank; care providers; career development; clinically significant; cohort; connective tissue growth factor; differential expression; drug repurposing; experimental study; in vivo; in vivo Model; innovation; interest; knock-down; molecular marker; mouse model; novel; overexpression; patient subsets; personalized approach; protein expression; response to injury; skills; targeted treatment; therapeutic target; transcriptome; transcriptome sequencing; treatment response; treatment strategy

PROJECT SUMMARY This R03 project emerges directly from studies described in Dr. Menard-Katcher’s K23 award. The proposed aims define a new direction of investigation within the broader goals of Dr. Menard-Katcher’s career development that will provide essential data, critical skills and important collaborations. Together these will provide a platform for R01 applications and complete research independence. Eosinophilic Esophagitis (EoE) is a chronic allergen mediated inflammatory esophageal disease with substantial and increasing burden in children and adults. Chronic inflammation classically leads to dysphagia. Mounting evidence identifies a subset of patients who develop clinically significant fibrosis and esophageal stricture, a phenotype identified to have more severe symptoms and worse treatment response. Termed fibrostenotic EoE (FS-EoE), this phenotype can be defined by partially occlusive stricture formation. Identifying those patients at greatest risk of fibrosis; determining optimal management strategies; and closing gaps in our understanding of the cellular pathways involved in the development of fibrotic disease are all needed to help provide tailored approach to therapy. Supported by Dr. Menard-Katcher’s K23, we evaluated and characterized over 110 pediatric EoE patients based on clinical outcomes, symptoms, endoscopic appearance, histology and esophageal function (ie distensibility). RNASeq analysis from a subset of these patients identified genes with altered expression that could define a FS-EoE phenotype. Gene pathway analysis identified SMAD protein phosphorylation pathways to be differentially expressed between fibrotic (with stricture) and non-fibrotic (without stricture) EoE subjects and specifically identified connective tissue growth factor (CTGF/CCN2) overexpression in the FS-EoE phenotype. CTGF (or CCN2) is a secreted regulatory matricellular protein involved in promoting fibrosis often through TGFß /SMAD in response to injury. CTGF is implicated in the progression of fibrosis in the kidney, lung and skin and it may be an amenable target for treatment. We hypothesize CTGF is involved in promoting fibrotic remodeling in EoE and that evaluation of the EoE proteome will identify novel proteins implicated in a more severe fibrotic phenotype. To address this overarching hypothesis, we propose two related but independent aims. As CTGF has not yet been explored in EoE or the esophagus, in Aim 1 we will determine CTGF expression in in vitro and in a novel in vivo model of EoE. In Aim 2 we will evaluate the esophageal mucosal proteome to identify targets and pathways implicated in the fibrostenotic phenotype. Results from the proposed Aims will elucidate if the CTGF pathway is implicated in EoE and use multi- omic data to identify novel pathways and targets for next step research in the pathogenesis and possible treatment of FS-EoE. This will provide novel evidence to support a successful R01 or similar application that will investigate biomechanisms of disease and innovative approaches to management of FS-EoE.

项目摘要 这个R 03项目直接来自Menard-Katcher博士的K23奖中描述的研究。拟议 目标在梅纳德-卡彻博士职业生涯的更广泛目标中定义了一个新的研究方向 这将提供必要的数据，关键技能和重要的合作。这些共同将 为R 01应用程序提供平台，并完全独立于研究。 嗜酸性食管炎（EoE）是一种慢性过敏原介导的炎症性食管疾病， 儿童和成人的负担越来越重。慢性炎症通常会导致吞咽困难。 越来越多的证据表明，一部分患者发生了临床显著的纤维化和食管癌。 狭窄，一种被鉴定为具有更严重症状和更差治疗反应的表型。称为 纤维狭窄性EoE（FS-EoE），这种表型可以通过部分闭塞性狭窄形成来定义。识别 这些患者的纤维化风险最大;确定最佳的管理策略;并缩小差距，我们的 了解纤维化疾病发展中涉及的细胞通路， 提供定制的治疗方法。在Menard-Katcher博士的K23的支持下，我们评估并表征了 根据临床结局、症状、内镜外观、组织学和 食管功能（即扩张性）。来自这些患者的一个子集的RNASeq分析鉴定了具有以下特征的基因： 改变的表达可以定义FS-EoE表型。基因通路分析鉴定SMAD蛋白 在纤维化（狭窄）和非纤维化之间差异表达的磷酸化途径 （无狭窄）EoE受试者和特异性鉴定的结缔组织生长因子（CTGF/CCN 2） FS-EoE表型中的过表达。 CTGF（或CCN 2）是一种分泌的调节性基质细胞蛋白，通常参与促进纤维化， 通过TGF β 1/SMAD对损伤的反应。CTGF与肾纤维化的进展有关， 肺和皮肤，它可能是一个适合治疗的目标。我们假设CTGF参与促进 EoE中纤维化重构和EoE蛋白质组的评估将鉴定与EoE中的纤维化重构相关的新蛋白质， 更严重的纤维化表型。为了解决这个总体假设，我们提出了两个相关的，但 独立的目标。由于CTGF尚未在EoE或食管中进行探索，因此在目标1中，我们将确定 CTGF在体外和EoE的新型体内模型中的表达。在目标2中，我们将评估食管 粘膜蛋白质组，以确定涉及纤维狭窄表型的靶点和途径。 来自所提出的目的的结果将阐明CTGF通路是否与EoE有关，并使用多个 组学数据，以确定新的途径和目标，为下一步研究的发病机制和可能的 治疗FS-EoE。这将提供新的证据来支持R 01或类似的成功应用， 将研究疾病的生物机制和FS-EoE管理的创新方法。