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A Novel Mechanism of Mast Cell-Nerve Interactions in the Esophagus

食管肥大细胞与神经相互作用的新机制

基本信息

批准号：
10093678
负责人：
Xinzhong Dong
金额：
$ 53.08万
依托单位：
JOHNS HOPKINS UNIVERSITY
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：
2020-09-21 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10093678
关键词：
Acids Acute Address Allergens Allergic Attenuated Biopsy Specimen C Fiber Cations Chronic Connective Tissue Cytoplasmic Granules Data Defensins Disease Eosinophil Granule Proteins Eosinophil cationic protein Eosinophilic Esophagitis Epithelial Epithelium Esophageal Diseases Esophagitis Esophagus Functional disorder Funding G-Protein-Coupled Receptors Gastroesophageal reflux disease Genome Heartburn Histology Human IgE Image Immunologics Inflammation Inflammatory Interleukin-5 Intestinal Mucosa Investigation Knowledge Lamina Propria Lead Location Mediating Mediator of activation protein Methodology Modeling Mucous Membrane Mus Nerve Neuroimmune Neurons Neuropeptides Nociception Pain Pathogenesis Peptic Esophagitis Permeability Phenotype Play Proteins Publishing Reaction Reflux Refractory Role Specimen Stratified Squamous Epithelium Substance P Symptoms Techniques Tryptase Wild Type Mouse cytokine eosinophil experimental study extracellular immune activation mRNA Expression mast cell mouse model new therapeutic target novel receptor recruit response tissue injury two-photon

项目摘要

Project Summary Marked increases in esophageal mast cells (MCs) have been identified not only in allergic but also in non-allergic esophageal disorders. At present, their roles in the pathogenesis of those disorders are still less clear. Unlike intestinal mucosal MCs, esophageal MCs are predominantly distributed in the lamina propria of the mucosa, whereas they are matured in non-keratinized stratified squamous epithelium and developed into distinctive phenotype. Recently, the Immunologic Genome (ImmGen) Project Consortium has classified esophageal MC as one of the typical connective tissue MCs. Moreover, our new study has identified that MrgprB2 (the orthologue of human MrgprX2) is a GPCR and exclusively expressed in connective tissue MCs. Many basic secretagogues (substance P, VIP, PAMP, defensins, et al) and eosinophil cationic proteins are now known to activate mast cells exclusively via MrgprB2/X2 mechanisms. Our published and preliminary studies are supporting the novel hypothesis that MrgprB2 (MrgprX2 in human) mediates esophageal inflammation-induced MC activation and directly contributes to esophageal epithelial barrier dysfunction and esophageal afferent nociceptive nerve hyperexcitability. We will address this hypothesis in the mouse and human esophagus with following aims. In Aim 1, we will characterize MrgprB2-positive MCs in healthy and inflamed esophagus with respects to their distribution, phenotype, and activation response (mediators/cytokines release) to basic secrectagogues. We will then address the hypothesis that MrgprB2 mediates non-IgE-dependent MC activation by comparing MC mediator release in inflamed esophagus in wild type and MrgprB2mut mice. Lastly, we will explore, in an eosinophilic esophagitis model, whether eosinophil granule basic proteins (MBP, EPO, END,) directly activate MrgprB2. In Aim 2, we will continue to advance our interesting preliminary data demonstrating that reflux-induced esophageal epithelial barrier dysfunction (increased permeability) is significantly attenuated in MrgprB2 mut mice. To determine if non-MrgprB2 mast cell activation mechanisms also contribute to barrier breakdown we will compare permeability changes in our reflux vs allergic esophagitis models in three groups of mice, wild type mice; mice where the mast cells do not express functional MrgprB2 mut; and thirdly mice that are mast cell deficient. In Aim 3, we will compare the effect of MrgprB2 vs allergen-evoked mast cell activation on esophageal nociceptive C-fiber terminal activities using our well-established extra-cellular recording techniques along with our newly-developed two-photon neuron imaging methodology. In Aim 4, we will compare the expression and function of MrgprX2 in human esophageal biopsy specimens from reflux and eosinophilic esophagitis and then determine their correlations with esophageal histology/symptoms. Translationally, we will briefly characterize MrgprX2 expression and function in mouse esophagus by using our newly-established humanized MrgprX2 mouse line. Clarifying MrgprB2/X2-mediated esophageal mast cell activation may motivate investigation of novel targeted therapeutic strategies for esophageal inflammatory disorders.

项目总结