Regulation of Allergic Inflammation by Histamine

组胺调节过敏性炎症

基本信息

批准号：
8663826
负责人：
PAUL J BRYCE
金额：
$ 42.32万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-02-01 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8663826
关键词：
Address Agonist Allergens Allergic Allergic Disease Allergic inflammation Antibodies B-Lymphocytes Bioinformatics Biological Biopsy Blood CCL24 gene CCL26 gene Cells Clinical Treatment Collaborations Collection Complex Cytokine Receptors Data Defect Diet Disease Eosinophilia Eosinophilic Esophagitis Epithelial Cells Epithelium Esophageal Family Food Gene Expression Profile Generations Genes Genetic HRH2 gene Hematopoietic Histamine Histamine Receptor Homeostasis Human IgE IgG1 Immune Immune response Immunity Immunoglobulin Class Switching In Vitro Inflammation Inflammatory Inflammatory Response Interferons Interleukin-12 Interleukin-13 Interleukin-4 Lung Maps Mediating Messenger RNA Modeling Molecular Mus Pathogenesis Pathway interactions Patients Pattern Phenotype Point Mutation Process Production Publishing Receptor Signaling Regulation Reporting Role Signal Transduction Signaling Molecule Staging Tissues Up-Regulation Work airway epithelium allergic response base chemokine cohort cytokine deep sequencing eosinophil eosinophilic inflammation genome-wide human disease interleukin-15 receptor mast cell mastocytosis novel public health relevance receptor receptor function response

项目摘要

DESCRIPTION (provided by applicant): Cytokines and their receptors have an incredible ability to regulate a diverse range of cellular responses, important for homeostasis and control of protective immune responses. Increasingly, context or cell-specific influences of cytokines are being observed but the mechanisms that regulate this remain unclear given the limited repertoire of intracellular signaling molecules within the Jak and Stat family. Recently, the concept of "modifiers" of cytokine receptor functions has emerged, whereby signals from other receptors can alter those through the cytokine receptor. Our exciting findings have established that histamine, acting via its receptor H2R, is necessary for cellular responses to IL-4. This cytokine is critically important in allergic responses and we have demonstrated that H2R KO mice have ablated IgE generation and eosinophil recruitment to the lungs. In studying this interaction further, we have identified that both hematopoietic and non-hematopoietic cells possess histamine-dependent and independent responsiveness to IL-4. We hypothesize that H2R functions as a modifier of signaling from the IL-4 receptor and is necessary for switching from the homeostatic functions of IL-4 to a pro- allergic response. We propose to examine this with three specific aims that investigate this concept in murine models and in allergic patients. Specific Aim 1 will examine the functional requirements for H2R on responses through the IL-4Ralpha chain (in collaboration with Dr Talal Chatila). Specific Aim 2 will map the unique profile of histamine-dependent and independent genes in human and murine cells using state-of-the-art mRNA deep sequencing (in collaboration with Dr Nadereh Jafari). Specific Aim 3 will examine histamine-associated gene patterns in the pathogenesis of eosinophilic esophagitis and build on our existing work demonstrating the mast cells and histamine are important in this disease.

描述（由申请人提供）：细胞因子及其受体具有不可思议的调节细胞反应范围的能力，对于稳态和保护性免疫反应的控制很重要。越来越多地观察到了细胞因子的上下文或细胞特异性影响，但是鉴于JAK和STAT家族中细胞内信号分子的库库有限，调节这种调节的机制尚不清楚。最近，已经出现了细胞因子受体功能的“修饰剂”概念，从而通过细胞因子受体来改变了其他受体的信号。我们令人兴奋的发现确定，通过其受体H2R作用的组胺对于对IL-4的细胞反应是必要的。这种细胞因子在过敏反应中至关重要，我们已经证明H2R KO小鼠对肺有消融的IgE产生和嗜酸性粒细胞募集。在进一步研究这种相互作用的过程中，我们已经确定造血和非山摩托质细胞都具有组胺依赖性和独立的反应性IL-4。我们假设H2R是来自IL-4受体的信号传导的修饰符，对于从IL-4的稳态函数转换为促响应是必不可少的。我们建议以三个特定的目的对此进行研究，以在鼠模型和过敏患者中调查这一概念。特定的目标1将检查H2R对通过IL-4Ralpha链的响应的功能要求（与Talal Chatila博士合作）。具体目标2将使用最先进的mRNA深度测序（与Nadereh Jafari博士合作），绘制人和鼠细胞中组胺依赖性和独立基因的独特曲线。具体目标3将在嗜酸性食管炎的发病机理中检查与组胺相关的基因模式，并建立在我们现有的工作中，证明肥大细胞和组胺在该疾病中很重要。