The Role of FOXM1 in Eosinophilic Esophagitis Pathogenesis

FOXM1 在嗜酸性食管炎发病机制中的作用

基本信息

批准号：
10724896
负责人：
Amanda Brooke Muir
金额：
$ 17.8万
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：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10724896
关键词：
3-Dimensional Acids Air Allergic Disease Allergic inflammation Antigens Award Basal Cell Hyperplasia Biological Assay Body Weight decreased CCL26 gene Cell Culture Techniques Cell Nucleus Cells Chemotactic Factors Chemotaxis Chronic Disease Clinical Cytoplasmic Granules Data Deglutition Deglutition Disorders Development Disease Disease remission Down-Regulation Endoscopy Eosinophilic Esophagitis Eosinophilic Infiltrate Epithelial Cells Epithelium Esophagus Evaluation Event FOXM1 gene Fibrosis Food Future Genes Genetic Goals Health Histologic Homeostasis Immune system In Vitro Incidence Inflammation Inflammatory Interleukin-13 Interleukin-4 Intracellular Space Invaded Knowledge Liquid substance Modeling Mucous Membrane Mus Organoids Pathogenesis Pathogenicity Pathologic Patients Persons Phosphorylation Proliferating Proteins Quality of life Refractory Regulation Research Role STAT6 Transcription Factor STAT6 gene Severity of illness Techniques Testing Therapeutic Tissues United States Up-Regulation Vomiting chromatin immunoprecipitation cytokine eosinophil eosinophilic inflammation forkhead protein granulocyte healing human disease in vivo mouse model novel particle pharmacologic segregation symptomatology therapeutic target transcription factor transcriptome treatment response treatment strategy

3-Dimensional Acids Air Allergic Disease Allergic inflammation Antigens Award Basal Cell Hyperplasia Biological Assay Body Weight decreased CCL26 gene Cell Culture Techniques Cell Nucleus Cells Chemotactic Factors Chemotaxis Chronic Disease Clinical Cytoplasmic Granules Data Deglutition Deglutition Disorders Development Disease Disease remission Down-Regulation Endoscopy Eosinophilic Esophagitis Eosinophilic Infiltrate Epithelial Cells Epithelium Esophagus Evaluation Event FOXM1 gene Fibrosis Food Future Genes Genetic Goals Health Histologic Homeostasis Immune system In Vitro Incidence Inflammation Inflammatory Interleukin-13 Interleukin-4 Intracellular Space Invaded Knowledge Liquid substance Modeling Mucous Membrane Mus Organoids Pathogenesis Pathogenicity Pathologic Patients Persons Phosphorylation Proliferating Proteins Quality of life Refractory Regulation Research Role STAT6 Transcription Factor STAT6 gene Severity of illness Techniques Testing Therapeutic Tissues United States Up-Regulation Vomiting chromatin immunoprecipitation cytokine eosinophil eosinophilic inflammation forkhead protein granulocyte healing human disease in vivo mouse model novel particle pharmacologic segregation symptomatology therapeutic target transcription factor transcriptome treatment response treatment strategy

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项目摘要

Project Summary Eosinophilic esophagitis (EoE) is a rare, chronic disorder characterized by persistent allergic inflammation that leads to fibrosis and stricture which effects about 150,000 people in the United States. Clinical manifestations include weight loss, vomiting, dysphagia, and food impaction, all of which dramatically impact patients' quality of life. Histologically, it is characterized by mucosal eosinophilic infiltration and esophageal epithelial remodeling events, specifically basal cell hyperplasia (BCH) and dilated intracellular spaces (DIS). These epithelial changes disrupt the mucosal barrier which normally provides protection from acid and food particles during normal swallows. In our preliminary data we have found that Forkhead box (FOX) M1 expression is increased in the esophagus of EoE patients. Further, FOXM1 is induced in the epithelium after stimulation with IL-13, the major effector cytokine in EoE. We have found that inhibition of FOXM1 in esophageal epithelial cell culture reduces epithelial perturbations in the setting of cytokine stimulation and reduces chemoattractant secretion. Based on these findings, we hypothesize that FOXM1 disrupts epithelial homeostasis and contributes to eosinophil chemotaxis in EoE We propose 2 aims in this application. The first aim will determine the mechanism by which FOXM1 disrupts epithelial homeostasis in the esophageal epithelium using 3D epithelial modeling techniques that are well established in the Muir Lab: organoid culture and air-liquid interface culture. We will induce EoE in mice and evaluate the effect of FOXM1 inhibition on disease severity and epithelial damage. We will compliment this with chromatin immunoprecipitation to identify differentially regulated targets of FOXM1. In the second aim we will define the role of FOXM1 in regulation of chemotaxis in the EoE epithelium. We have found that pharmacological inhibition of FOXM1 leads to downregulation of both total and phosphorylated STAT6 protein, as well as CCL26 (the gene encoding Eotaxin-3, the key chemoattractant for eosinophils in EoE). We will test whether FOXM1 inhibition interferes with eosinophil chemotaxis in vitro and in vivo. Thisinnovative and hypothesis-driven study is backed by strong preliminary data generated by the PI. The PI is uniquely poised to accomplish these aims with her previous track record in investigating mechanisms of epithelial inflammation in EoE using 3D epithelial culture and murine models.

项目摘要嗜酸性食管炎（EOE）是一种罕见的慢性疾病，其特征是持续过敏导致纤维化和狭窄的炎症在美国影响约15万人。临床表现包括体重减轻，呕吐，吞咽困难和食物影响，所有这些都极大地影响患者的生活质量。在组织学上，它的特征是粘膜嗜酸性浸润和食管上皮重塑事件，特别是基底细胞增生（BCH）和扩张的细胞内空间（DIS）。这些上皮变化破坏了通常提供酸和食物保护的粘膜屏障正常燕子期间的颗粒。在我们的初步数据中，我们发现叉子盒（FOX）M1表达式 EOE患者的食道中有所增加。此外，刺激后，在上皮中诱导FOXM1 IL-13，EOE中的主要效应细胞因子。我们发现抑制FOXM1在食管上皮细胞中培养在细胞因子刺激的情况下减少上皮扰动并降低趋化剂分泌。根据这些发现，我们假设FOXM1破坏了上皮稳态并贡献 EOE中的嗜酸性粒细胞趋化性我们在此应用程序中提出了2个目标。第一个目标将确定FOXM1的机制使用3D上皮建模技术破坏食管上皮的上皮稳态在Muir实验室中良好建立：器官培养和空气界面培养。我们将在小鼠中诱导EOE，评估FOXM1抑制对疾病严重程度和上皮损害的影响。我们会赞美这一点染色质免疫沉淀以鉴定FOXM1的差异调节靶标。在第二个目标中，我们将定义FOXM1在EOE上皮中趋化性调节中的作用。我们发现药理学 FOXM1的抑制会导致总和磷酸化的STAT6蛋白以及CCL26的下调（编码Eotaxin-3的基因，EOE中嗜酸性粒细胞的关键趋化剂）。我们将测试FOXM1是否抑制作用在体外和体内干扰嗜酸性粒细胞趋化性。这项挖掘和假设驱动的研究得到了PI产生的强烈初步数据的支持。 PI唯一准备通过她以前的研究机制来实现这些目标 EOE中使用3D上皮培养和鼠模型的上皮炎症。