Maturational Characterization of Human Esophageal Fibroblasts in EoE

EoE 中人食管成纤维细胞的成熟特征

• 批准号: 8594772
• 负责人: Amanda Brooke Muir
• 金额: $ 6.27万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8594772
• 关键词: 3-Dimensional; Adult; Affect; Age; Allergic Disease; Allergic inflammation; Bile Acids; Biopsy; Bolus Infusion; Cell Culture Techniques; Cell Line; Cells; Characteristics; Childhood; Chronic; Chronic Disease; Cicatrix; Complication; Conditioned Culture Media; Data; Deglutition Disorders; Dermal; Diagnosis; Disease; Eosinophilic Esophagitis; Epithelial; Epithelial Cells; Epithelium; Esophageal; Esophageal Dysphagia; Esophageal Tissue; Esophagus; Fibroblasts; Fibrosis; Food; Human; In Vitro; Infiltration; Inflammation; Lead; Life; Mesenchymal; Modeling; Myofibroblast; Natural History; Patients; Population; Recurrence; Reporting; Stimulus; TNF gene; Tissues; age group; age related; cytokine; disease natural history; eosinophil; epithelial to mesenchymal transition; fetal; food antigen; migration; novel; prevent; public health relevance; release factor; response

DESCRIPTION (provided by applicant): Eosinophilic esophagitis (EoE) is an allergic disease characterized by esophageal infiltration of eosinophils, diagnosed from childhood through adulthood. Esophageal fibrosis is the most serious complication of EoE, leading to dysphagia and esophageal food impaction starting in the second decade of life. Elucidating the mechanisms which lead to fibrosis is critical to understanding the natural history of EoE. Our preliminary data suggests that cross-talk between primary EoE esophageal epithelial cells (EPCs) and primary fetal esophageal fibroblast cells (FEF3) enhances FEF3 expression of profibrotic cytokines. However, our model is limited by its use of fetal fibroblasts, which are functionally distinct from pediatric and adult fibroblasts. To date, characterization of esophageal fibroblasts spanning pediatric and adult EoE populations has never been described. Our overall hypothesis is that esophageal fibroblasts from EoE subjects are phenotypically distinct from fibroblasts from non-EoE subjects, and that fibro genic characteristics of EoE fibroblasts are enhanced during human maturation. Using primary esophageal fibroblasts, we will characterize fibroblast cytokine responses and contractility, comparing responses between age-matched EoE and non-EoE subjects (Aim 1a). Age-related differences in fibrotic responses in EoE subjects ages 1-9 years, 10-17 years, and adults will be examined (Aim 1b). We will determine fibroblast responses to epithelial-derived factors in the context of physiologically relevant epithelial stimuli including acid/bile and EoE triggers (food antigens) (Aim 2a). Finally, the effects of these stimuli upon fibrosis will be examined using novel organotypic cell culture models of "living" esophageal tissue, constructed from primary EPCs and esophageal fibroblast cell lines (Aim 2b).

描述（由申请人提供）：嗜酸性粒细胞性食管炎（EoE）是一种以食管嗜酸性粒细胞浸润为特征的过敏性疾病，从儿童期到成年期均有诊断。食管纤维化是 EoE 最严重的并发症，从生命的第二个十年开始导致吞咽困难和食管食物嵌塞。阐明导致纤维化的机制对于理解 EoE 的自然史至关重要。我们的初步数据表明，原代EoE食管上皮细胞（EPC）和原代胎儿食管成纤维细胞（FEF3）之间的串扰增强了促纤维化细胞因子的FEF3表达。然而，我们的模型因其使用胎儿成纤维细胞而受到限制，胎儿成纤维细胞在功能上与儿科和成人成纤维细胞不同。迄今为止，食管的特征 跨越儿童和成人 EoE 群体的成纤维细胞从未被描述过。我们的总体假设是，EoE 受试者的食管成纤维细胞在表型上与非 EoE 受试者的成纤维细胞不同，并且 EoE 成纤维细胞的纤维形成特征在人类成熟过程中增强。使用原代食管成纤维细胞，我们将表征成纤维细胞细胞因子反应和收缩性，比较年龄匹配的 EoE 和非 EoE 受试者之间的反应（目标 1a）。将检查 1-9 岁、10-17 岁和成人的 EoE 受试者纤维化反应与年龄相关的差异（目标 1b）。我们将在生理相关的上皮刺激（包括酸/胆汁和 EoE 触发器（食物抗原））的背景下确定成纤维细胞对上皮衍生因子的反应（目标 2a）。最后，将使用由原代 EPC 和食管成纤维细胞系构建的新型“活”食管组织器官型细胞培养模型来检查这些刺激对纤维化的影响（目标 2b）。