Measurement and Molecular Mechanisms of Altered Esophageal Distensibility

食管扩张性改变的测量和分子机制

基本信息

批准号：
10439751
负责人：
MARIE-PIER TETREAULT
金额：
$ 37.72万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-15 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10439751
关键词：
3-Dimensional Achalasia Affect Aftercare Animal Model Atrophic Biological Markers Biological Process Biomechanics Biopsy Bleomycin Bolus Infusion Budesonide Caring Cell Survival Cellular biology Characteristics Choking Computer Models Coupled Development Devices Diagnosis Dilatation - action Dimensions Disease Elements Endoscopy Engineering Eosinophilic Esophagitis Epithelial Epithelial Cells Esophageal Diseases Esophageal mucous membrane Esophagogastric Junction Esophagus Fibrosis Food Functional disorder Future Gastroesophageal reflux disease Goals Histologic Human Hydromorphone I Kappa B-Alpha Immunity Impairment Individual Inflammation Inflammation Mediators Inflammatory Inflammatory Response Investigation Ireland Manometry Measurement Measures Mechanics Mediating Methodology Molecular Morbidity - disease rate Mucous Membrane Mus Muscular Atrophy NF-kappaB-inducing kinase Obstruction Operative Surgical Procedures Organoids Ovalbumin Pathogenesis Pathway interactions Patients Pattern Phenotype Process Reflux Regulation Reporting Research Resolution Role Schools Scleroderma Signal Transduction Smooth Muscle Smooth Muscle Myocytes Stat3 protein Stimulus Submucosa Systemic Scleroderma Technology Testing Time Tissues Transgenic Mice Translational Research cell growth chemokine commercialization cytokine design egg electric impedance eosinophilic inflammation esophagus pressure imaging probe in silico industry partner instrument mouse model neuromuscular function novel novel strategies pressure simulation standard of care therapeutic target

项目摘要

PROJECT SUMMARY A common element mediating the morbidity of esophageal disorders is altered distensibility of the esophageal wall, potentially resulting in impaired food transit, episodic choking, esophageal retention, and aspiration. In this proposal we will develop novel methodologies to quantify esophageal wall distensibility in disease states characterized by either increased or decreased distensibility, phenotype patients accordingly, obtain mucosal biopsies, and investigate the corresponding molecular mechanisms. Patients with eosinophilic esophagitis (EoE), scleroderma (SSc), and achalasia will be studied using functional luminal imaging probe (FLIP) topography and 4D impedance manometry (4D-IM) before and after standard of care (SOC) treatment (or in conjunction with SOC care and Bravo pH-metry in the case of SSc). Our overarching goal is to understand the molecular mechanisms leading to altered esophageal luminal distensibility through mechanistic studies of key mediators of inflammation: inhibitor of nuclear factor kappa-B kinase subunit beta (IKKβ) and signal transducer and activator of transcription 3 (STAT3). The significance of this proposal lies in: 1) expanding our understanding of esophageal disease pathogenesis from a one-dimensional focus on neuromuscular function to a comprehensive study of esophageal wall mechanics as the determinant of function and dysfunction; and 2) the central roles of epithelial IKKβ and epithelial STAT3 signaling in the regulation of diverse biological processes, such as inflammation, immunity, cell survival, and cell growth. The projects leaders have expertise in esophageal pathophysiology, translational research, animal models of esophageal disease, cell signaling, and epithelial cell biology. Here, we will test the hypothesis that altered esophageal distensibility is mediated through differential IKKβ activation in the esophageal mucosa triggered by either eosinophilic inflammation in EoE or abnormal luminal pressurization in achalasia and that STAT3 signaling promotes esophageal smooth muscle atrophy in SSc. To explore these processes, we will undertake three interrelated Specific Aims. In Aim 1, we will investigate epithelial IKKβ/NFκB and STAT3 signaling as modulators of altered esophageal luminal distensibility in EoE, SSc, and achalasia using mucosal biopsies in patients phenotyped using FLIP topography and 4D-IM as well as Bravo pH-metry in the case of SSc. In Aim 2, we will determine the role of epithelial IKKβ signaling in promoting fibrosis in EoE. Here, we will utilize a novel transgenic mouse model with esophageal epithelial IKKβ deletion treated with egg ovalbumin, and 3D organotypic culture. In Aim 3, we will determine the requirement for epithelial STAT3 signaling in promoting esophageal smooth muscle cell loss in SSc esophageal disease. This will be undertaken with a new transgenic mouse model of SSc (esophageal epithelial STAT3 deletion treated with bleomycin). We anticipate that these studies will identify factors leading to abnormal esophageal luminal distensibility in these disease states that may serve as future therapeutic targets.

项目概要介导食管疾病发病的一个常见因素是食管扩张性的改变壁，可能导致食物运输受损、偶发性窒息、食管滞留和误吸。根据该提案，我们将开发新的方法来量化疾病状态下的食管壁扩张性以扩张性增加或减少为特征，相应地表型患者获得粘膜活检，并研究嗜酸性食管炎患者的相应分子机制。 (EoE)、硬皮病 (SSc) 和贲门失弛缓症将使用功能性管腔成像探针 (FLIP) 进行研究标准护理 (SOC) 治疗前后（或治疗中）进行地形图和 4D 阻抗测压 (4D-IM) 在 SSc 的情况下与 SOC 护理和 Bravo pH 测量相结合）我们的首要目标是了解通过关键的机械研究导致食管管腔扩张性改变的分子机制炎症介质：核因子 kappa-B 激酶亚基 β (IKKβ) 抑制剂和信号转导器和转录激活子3（STAT3）。该提案的意义在于：1）扩展了我们的研究范围。从一维神经肌肉功能认识食管疾病发病机制全面研究食管壁力学作为功能和功能障碍的决定因素； 2）上皮IKKβ和上皮STAT3信号在多种生物调节中的核心作用项目负责人拥有专业知识，例如炎症、免疫、细胞存活和细胞生长。食管病理生理学、转化研究、食管疾病动物模型、细胞信号传导、和上皮细胞生物学，我们将检验食管扩张性改变是介导的假设。通过食管粘膜中由嗜酸性粒细胞炎症引发的差异性 IKKβ 激活 EoE 或贲门失弛缓症的异常管腔加压以及 STAT3 信号传导促进食管平滑为了探索这些过程，我们将采取三个相互关联的具体目标。目标 1，我们将研究上皮 IKKβ/NFκB 和 STAT3 信号传导作为食管改变的调节剂使用 FLIP 表型患者的粘膜活检，评估 EoE、SSc 和贲门失弛缓症的管腔扩张性地形和 4D-IM 以及 Bravo pH 测量在 SSc 中的作用在目标 2 中，我们将确定上皮 IKKβ 信号传导促进 EoE 纤维化在这里，我们将利用一种新型转基因小鼠模型。在目标 3 中，我们用卵清蛋白处理食管上皮 IKKβ 缺失，并进行 3D 器官型培养。将确定上皮 STAT3 信号传导在促进食管平滑肌细胞损失中的需要这将通过一种新的 SSc 转基因小鼠模型（食管病）进行。我们预计这些研究将确定导致上皮细胞 STAT3 缺失的因素。这些疾病状态下的异常食管管腔扩张性可能作为未来的治疗方法目标。