Expression and Modulation of Mast Cell Function in Asthma

哮喘中肥大细胞功能的表达和调节

基本信息

批准号：
8072934
负责人：
Stephen Joseph Galli
金额：
$ 8.32万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-03 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8072934
关键词：
2,4-Dinitrophenol Abbreviations Acute Affinity Allergic inflammation Aluminum Hydroxide Alveolar Antibodies Antigens Asthma Bone Marrow Bromodeoxyuridine C57BL/6 Mouse Cell physiology Cells Chronic Chymase Congenic Mice Contact hypersensitivity Cytotoxic T-Lymphocytes Dependence Dermal Development Dinitrophenols Disease Management Endothelin-1 Enzymes Experimental Autoimmune Encephalomyelitis Fluorescein Fluorescein-5-isothiocyanate Fluoresceins Functional disorder Funding G-Protein-Coupled Receptors Guanine Nucleotide Exchange Factors Hematoxylin and Eosin Staining Method Histocytochemistry Human IgE Receptors Individual Inflammation Inflammatory Response Interferon Type II Interferons Interleukin-3 Irrigation Isothiocyanates Knock-in Mouse Knock-out Leukocytes Leukotrienes Lung Major Histocompatibility Complex Mediation Membrane Modeling Monoclonal Antibodies Mus Mutant Strains Mice Nose Nucleotides Ovalbumin Oxazolone Passive Cutaneous Anaphylaxis Peritoneal Process Proto-Oncogene Protein c-kit Protocols documentation Resistance Role Serum Albumin Stem Cell Factor T-Cell Receptor TNF gene Testing Tissues Tumor Necrosis Factor-alpha Tumor Necrosis Factors Venous Wild Type Mouse airway hyperresponsiveness aluminum sulfate cell type embryonic stem cell eosinophil in vivo mast cell methacholine mouse model mutant neutrophil novel strategies progenitor progesterone 11-hemisuccinate-(2-iodohistamine)receptor response small hairpin RNA

项目摘要

DESCRIPTION (provided by applicant): We hypothesize that mast cells (MCs) can have direct and indirect effects which can significantly enhance the local development of antigen- (Ag-) induced inflammatory responses in the airways, as well as the structural and functional consequences of such processes in the lungs. Specifically, we hypothesize that, in certain mouse models of acute or chronic allergic inflammation involving the lungs, MC activation by both antibody- (Ab-)dependent and Ab-independent mechanisms results in net effects which can contribute significantly to the development and/or enhancement of the inflammation, airway hyperreactivity (AHR) and tissue remodeling associated with these "asthma models", and that many such effects are promoted by MC- associated TNF and can be enhanced by interferon gamma (IFNgamma), acting via IFNgamma receptors (IFNgammaRs) on MCs. We will test these hypotheses by using different protocols that can elicit either acute or chronic models of asthma in mice. We will examine genetically MC-deficient c-kit mutant mice (WBB6F1-KitW/W-v mice and C57BL/6- KitW-sh/W-sh mice) the congenic Kit+/+ wild type (WT) mice and "MC knock-in mice", i.e., c-kit mutant mice which have been selectively engrafted with WT MCs or MCs which express genetically-determined abnormalities in the expression of products which we hypothesize are involved in the activation, modulation or mediation of MC function. By assessing the extent to which key features of these asthma models differ in c-kit mutant MC-deficient and WT mice, we can quantify the c-kit-dependence of the responses. By determining to what extent any abnormalities in the expression of the responses in c-kit mutant mice are "normalized" or otherwise altered when such mice have been selectively engrafted with WT or genetically-manipulated MCs, we can assess the contribution of MCs, as well as individual MC products, including membrane-associated or soluble TNF, IFNgammaR1 or certain G protein-coupled receptors, to the expression of these features of the responses. By understanding better the mechanisms by which MCs can enhance the development of important features of asthma models in mice, and the mechanisms which influence the extent to which MCs can be activated to express their function in these settings, we will broaden the view of the potential roles of MCs in the development and progression of asthma in humans, and perhaps suggest new approaches for the management of this disorder.

描述（由申请人提供）：我们假设肥大细胞（MC）可以产生直接和间接的作用，可以显着增强抗原（Ag）诱导的气道炎症反应的局部发展，以及结构和功能后果肺部的此类过程。具体来说，我们假设，在某些涉及肺部的急性或慢性过敏性炎症的小鼠模型中，通过抗体（Ab）依赖性和Ab非依赖性机制激活MC会产生净效应，这可以显着促进疾病的发展和/或与这些“哮喘模型”相关的炎症、气道高反应性 (AHR) 和组织重塑的增强，并且许多此类作用是由 MC 相关的 TNF 促进的，并且可以通过干扰素 γ (IFNgamma) 增强，通过作用MC 上的 IFNgamma 受体 (IFNgammaR)。我们将通过使用不同的方案来测试这些假设，这些方案可以在小鼠中引发急性或慢性哮喘模型。我们将检查遗传性 MC 缺陷的 c-kit 突变小鼠（WBB6F1-KitW/W-v 小鼠和 C57BL/6- KitW-sh/W-sh 小鼠）、同类 Kit+/+ 野生型 (WT) 小鼠和“MC 敲入”小鼠小鼠”，即选择性植入 WT MC 或 MC 的 c-kit 突变小鼠，这些小鼠在产物表达中表达遗传决定的异常，我们假设是参与 MC 功能的激活、调节或介导。通过评估这些哮喘模型的关键特征在 c-kit 突变 MC 缺陷小鼠和 WT 小鼠中的差异程度，我们可以量化反应的 c-kit 依赖性。通过确定当 c-kit 突变小鼠选择性植入 WT 或基因操作 MC 时，c-kit 突变小鼠中反应表达的任何异常在多大程度上“正常化”或以其他方式改变，我们可以评估 MC 的贡献，如以及单独的 MC 产品，包括膜相关或可溶性 TNF、IFNgammaR1 或某些 G 蛋白偶联受体，以表达这些反应特征。通过更好地了解 MC 增强小鼠哮喘模型重要特征发育的机制，以及影响 MC 在这些环境中被激活以表达其功能的程度的机制，我们将拓宽潜在的视野MCs 在人类哮喘发生和进展中的作用，或许为治疗这种疾病提供了新的方法。