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Lysyl oxidase induced esophageal remodeling in eosinophilic esophagitis

赖氨酰氧化酶诱导嗜酸粒细胞性食管炎的食管重塑

基本信息

批准号：
10597600
负责人：
Amanda Brooke Muir
金额：
$ 39.6万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
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：
2020-06-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10597600
关键词：
3-Dimensional Affect Allergic inflammation Antibodies Award Basal Cell Hyperplasia Biological Assay Biology Caliber Cell Proliferation Cells Cellular Assay Chronic Chronic Disease Cicatrix Clinical Coculture Techniques Collagen Coupled Data Defect Development Diagnosis Disease Down-Regulation Drug Delivery Systems Early Diagnosis Enzymes Eosinophilic Esophagitis Eosinophilic Infiltrate Epithelial Attachment Epithelium Esophageal Stenosis Esophageal mucous membrane Esophagus Evaluation Event Feedback Fibroblasts Fibrosis Flow Cytometry Fluorescence-Activated Cell Sorting Future Gene Expression Profiling Human Immune Impairment In Vitro Infiltration Inflammation Knowledge Lamina Propria Lead Mediating Mediator Modeling Monitor Mucous Membrane Mus Myofibroblast Organoids Pathogenesis Pathologic Pathway interactions Patients Prevention Production Proliferating Protein-Lysine 6-Oxidase Proteins Quality of life Receptor Inhibition Regulation Reporting Role Signal Transduction Source Structure Symptoms System Therapeutic Therapeutic Uses Thick Time Tissues Transcriptional Regulation Transforming Growth Factors United States National Institutes of Health Work career chromatin immunoprecipitation clinical application cohort crosslink cytokine disability eosinophil food allergen healing improved in vivo inflammatory milieu innovation keratinocyte mast cell mouse model overexpression pharmacologic pre-clinical prognostic prognostic value reconstitution targeted treatment three dimensional cell culture transdifferentiation

项目摘要

Project Summary Eosinophilic esophagitis (EoE) is a chronic, debilitating disorder characterized by persistent allergic inflammation that over time leads to fibrosis and stricture. While it is characterized by intense eosinophil and mast cell infiltration, pathologic tissue remodeling events lead to irreversible fibrosis and significant clinical symptoms. These remodeling events include epithelial basal cell hyperplasia and subepithelial fibrosis. Our previous work has implicated lysyl oxidase (LOX), an enzyme known to cross-link collagen and potentiate tissue stiffness, as a key mediator of pathologic esophageal remodeling. LOX is robustly expressed in the esophageal mucosa of patients with active EoE inflammation, particularly in those with fibrosis. Robust in vitro and in vivo data suggest that TGF signaling in esophageal epithelium enhances LOX production, which in turn, promotes remodeling in both the epithelial (basal cell hyperplasia) and fibroblast compartments. We therefore seek to define the mechanisms whereby epithelial TGF and LOX promote remodeling in the esophagus and further exploit these mechanisms for clinical application. We hypothesize that the epithelial TGF-LOX axis drives basal cell hyperplasia and fibrostenosis in EoE. In Aim 1, we will evaluate the cell autonomous effects of epithelial LOX, evaluating how epithelial TGF drives LOX-induced basal cell hyperplasia in 3D epithelial culture and chromatin immunoprecipitation assays. In Aim 2, we will evaluate the non-cell autonomous effects of epithelial TGF and LOX by evaluating their effects on fibroblast activation and tissue stiffness. And finally, in Aim 3 we will evaluate the therapeutic and prognostic potential of this pathway by performing pre-clinical proof of purpose studies, treating mice with EoE inflammation with anti-TGF antibody and validating LOX expression in EoE patient tissue. Data from this study will inform future therapies targeting tissue remodeling as well as work towards identifying patients with fibrotic disease prior to the onset of disability. This innovative and hypothesis-driven study is backed by strong preliminary data generated by the PI while she was supported by an NIH career K08 award. The PI is uniquely poised to accomplish these aims with her previous track record in investigating mechanisms of epithelial-fibroblast crosstalk, LOX in EoE, and 3D epithelial culture and co-culture models.

项目摘要嗜酸性粒细胞性食管炎是一种慢性、使人衰弱的疾病，其特征是持续的过敏性随着时间的推移导致纤维化和狭窄的炎症。虽然它的特点是强烈的嗜酸性粒细胞和肥大细胞浸润、病理性组织重塑事件导致不可逆的纤维化和显著的临床症状这些重塑事件包括上皮基底细胞增生和上皮下纤维化。我们以前的研究已经涉及赖氨酰氧化酶（LOX），一种已知的交联胶原蛋白和增强组织的酶僵硬，作为病理性食管重塑的关键介质。LOX在食管癌组织中强烈表达，在具有活动性EoE炎症的患者的粘膜中，特别是在具有纤维化的那些中。体外和体内稳健性数据表明，食管上皮中的TGF β信号传导增强LOX的产生，进而促进上皮细胞（基底细胞增生）和成纤维细胞室的重塑。因此，我们力求明确上皮TGF β 1和LOX促进食管重塑的机制，将这些机制用于临床应用。我们假设上皮细胞TGF β-LOX轴驱动基底细胞细胞增生和纤维狭窄。在目标1中，我们将评估上皮细胞的细胞自主效应。 LOX，评估上皮TGF β如何在3D上皮培养中驱动LOX诱导的基底细胞增生，染色质免疫沉淀测定。在目标2中，我们将评估上皮细胞的非细胞自主效应。通过评估TGF β 1和LOX对成纤维细胞活化和组织硬度的影响来观察它们的作用。最后，在目标3中，将通过进行临床前目的证明来评估该途径的治疗和预后潜力研究，用抗TGF β 1抗体治疗患有EoE炎症的小鼠，并验证EoE中LOX的表达患者组织。这项研究的数据将为未来针对组织重塑的治疗提供信息，致力于在残疾发生之前识别患有纤维化疾病的患者。这项创新和假设驱动的研究得到了PI生成的强大初步数据的支持同时她获得了美国国立卫生研究院的K 08职业奖。PI是唯一准备实现这些目标，她以前在研究上皮成纤维细胞串扰机制、EoE中的LOX和3D方面的记录上皮培养和共培养模型。