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

基本信息

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
项目类别：
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

项目摘要

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R03项目直接来自Menard-Katcher博士K23奖中描述的研究。提议目标在Menard-Katcher博士的职业生涯的更广泛目标中定义了新的投资方向开发将提供基本数据，关键技能和重要合作。这些愿意在一起为R01应用程序提供平台和完整的研究独立性。嗜酸性食管炎（EOE）是一种慢性过敏原炎性食管疾病，儿童和成人的大量燃烧量增加。慢性炎症经典导致吞咽困难。越来越多的证据识别出临床上显着纤维化和食管的一部分患者狭窄，一种表型，被确定具有更严重的症状和较差的治疗反应。称为纤维雌激素EOE（FS-EOE），该表型可以通过部分遮挡的狭窄形成来定义。识别那些患有纤维化风险最大的患者；确定最佳管理策略；并缩小我们的差距需要了解纤维化疾病发展所涉及的细胞途径以帮助提供量身定制的治疗方法。在Menard-Katcher博士的K23的支持下，我们进行了评估和表征基于临床结果，症状，内窥镜外观，组织学和组织学和110多名儿科EOE患者食管功能（即令人讨厌）。来自这些患者的子集的RNASEQ分析鉴定出具有改变表达可以定义FS-EOE表型。基因途径分析确定了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，并特别鉴定出结缔组织生长因子（CTGF/CCN2） FS-EOE表型中的过表达。 CTGF（或CCN2）是一种分泌的调节基体蛋白，参与促进纤维化通过TGFß /SMAD响应伤害。 CTGF在肾脏的纤维化进展中暗示肺和皮肤，它可能是治疗的可正常靶标。我们假设CTGF参与促进 EOE中的纤维化重塑以及对EOE蛋白的评估将鉴定在A中实施的新型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假设独立目标。由于尚未在EOE或食管中探索CTGF，因此在AIM 1中，我们将确定 CTGF在体外和新型的EOE体内模型中的表达。在AIM 2中，我们将评估食管粘膜蛋白质组识别纤维固醇表型中实现的靶标和途径。提出的目标的结果将阐明是否在EOE中实现了CTGF途径并使用多种 OMIC数据以识别新的途径和目标，以进行发病机理的下一步研究 FS-EOE的处理。这将提供新的证据，以支持成功的R01或类似应用将研究疾病的生物力学和FS-EOE管理的创新方法。