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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.

项目总结引起食道疾病发病率的一个共同因素是食道的扩张性改变。胃壁，可能导致食物转运障碍、间歇性窒息、食道滞留和吸入。在……里面在这项提议中，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的，表型患者相应地获得粘膜活检，并研究相应的分子机制。嗜酸性食管炎患者 (EoE)、硬皮病(SSC)和失弛缓症将使用功能性管腔成像探头(FliP)进行研究。标准护理(SOC)治疗前后的地形图和4D-IM(4D-IM) 在SSC的情况下，结合SOC CARE和Bravo pH测量)。我们的首要目标是了解通过KEY机制研究导致食管腔扩张性改变的分子机制炎症介质：核因子-kappaB激酶亚单位β抑制物(IKKβ)和信号转导转录激活子3(STAT3)。这项建议的意义在于：1)扩大我们的从神经肌肉功能的一维角度认识食管病的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；以及 2)上皮性IKKβ和上皮性STAT3信号在多种生物调控中的中心作用炎症、免疫、细胞存活和细胞生长等过程。项目负责人具有专业知识在食道病理生理学、翻译研究、食道疾病的动物模型、细胞信号转导、和上皮细胞生物学。在这里，我们将检验一种假设，即改变的食道扩张性是由通过不同的IKKβ激活在食道粘膜中由嗜酸性炎症触发幽门失弛缓症患者的EoE或异常管腔压力及STAT3信号促进食道顺畅自发性硬化症的肌肉萎缩。为了探索这些进程，我们将实现三个相互关联的具体目标。在……里面目的1，我们将研究上皮IKKβ/NFκB和STAT3信号在食道病变中的调节作用用翻转表型法检测EoE、SSc和贲门失弛缓症患者粘膜活检的管腔扩张性在SSC的情况下，地形和4D-IM以及Bravo pH测量。在目标2中，我们将确定上皮性IKKβ信号在促进EoE纤维化中的作用。在这里，我们将利用一种新的转基因小鼠模型用卵清蛋白处理食道上皮细胞IKKβ缺失，并进行3D器官型培养。在目标3中，我们将决定上皮细胞STAT3信号在促进食道平滑肌细胞丢失中的需求在SSc食道疾病中。这将通过一种新的SSC(食道)转基因小鼠模型进行用博莱霉素治疗上皮性STAT3缺失)。我们预计，这些研究将确定导致这些疾病状态下异常的食管腔扩张性，可能作为未来的治疗方法目标。