Novel strategies for asthma therapy by regulating mast cell signaling by MyD88

通过 MyD88 调节肥大细胞信号传导治疗哮喘的新策略

基本信息

批准号：
7659253
负责人：
Hydar Ali
金额：
$ 19.69万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2011-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7659253
关键词：
Affect Affinity Air Allergens Allergic Allergic Reaction Allergic rhinitis American Antigens Asthma Binding Bone Marrow Bronchoconstriction C-terminal Cell Degranulation Cell physiology Child Complex Data Death Domain Developed Countries Development Disease Dust Endotoxins Environmental Pollutants Environmental Risk Factor Epithelial Cells Epithelium Family Generations Greater sac of peritoneum Histamine Release Household Human IgE IgE Receptors Immune response In Vitro Infiltration Inflammation Inflammation Mediators Inflammatory Interleukin-1 Interleukin-1 Receptors Interleukins Leukocytes Leukotrienes Lipids Lipopolysaccharides Lung Inflammation Lung diseases MAP Kinase Gene MAPK14 gene Mediating Mediator of activation protein Modeling Mus Myelogenous N-terminal Nose Orphan Pathogenesis Phosphorylation Play Population Prevalence Production Proto-Oncogene Proteins c-akt Pruritus Regulation Respiratory System Retroviridae Rhinitis Role SH2-Binding Motif Severities Signal Pathway Signal Transduction Sneezing Societies Symptoms Testing Th2 Cells Tyrosine Phosphorylation Up-Regulation Wheezing airway hyperresponsiveness base cytokine eosinophil expectation in vivo interest mast cell neutrophil novel novel strategies novel therapeutic intervention public health relevance receptor receptor function reconstitution response src Homology Domains toll-like receptor 4

项目摘要

DESCRIPTION (provided by applicant): Asthma is a complex airway inflammatory disease characterized by bronchoconstriction, airway hyperresponsiveness and inflammation. There is a substantial body of evidence that demonstrates an important role for mast cell high affinity IgE receptor (FceRI) in the pathogenesis of asthma. Therefore, tremendous efforts have been directed towards understanding the signaling pathway via which function of this receptor is regulated. Emerging evidence suggests that epithelial cell-derived cytokine such as interleukin-33 (IL-33) and bacterial lipopolysaccharide (LPS) play important roles in asthma exacerbation via the activation of their respective receptors ST2 and TLR4 but the mechanisms of their action remains unknown. Myeloid differentiation factor (MyD) 88 is the most proximal adapter molecule that transmits signal for both IL-33 and LPS. We made the novel observation that MyD88 not only regulates IL-33 and LPS signaling in mast cells, it also contributes to antigen/IgE-mediated protein kinase B (Akt) phosphorylation and cytokine production. We also found that LPS or IL-33 synergizes with antigen/IgE for cytokine generation and that this cross-talk is almost abolished in MyD88-/- mast cells. Based on these findings, we hypothesize that MyD88 promotes allergic inflammation by regulating and cross-regulating Fc5RI signaling in mast cells. Two specific aims are proposed to further explore the role of MyD88 on mast cell signaling in vitro and murine model of allergic inflammation in vivo. In aim #1, we will use retrovirus to transfect MyD88-/- mast cells with wild-type or genetically modified MyD88 to delineate how this adapter molecule regulates and cross-regulates FceRI signaling in mast cells. In aim #2, we will first test the hypothesis that MyD88 expressed in mast cells mediates allergic inflammation in vivo. We will then modulate MyD88 signaling in mast cells and determine the impact of this modulation on allergic inflammation. We believe that proposed studies will generate significant new information on the regulation and cross-regulation of FceRI signaling in mast cells and may offer novel therapeutic approaches for the treatment of asthma and other allergic diseases. PUBLIC HEALTH RELEVANCE: Asthma is a complex airway inflammatory disease characterized by bronchoconstriction, airway hyperresponsiveness and inflammation. Approximately 17 million Americans are estimated to have asthma, one third of them children. In recent years, asthma prevalence and severity have been increasing dramatically world-wide. Mast cells release inflammatory mediators that cause the symptoms of asthma and other allergic diseases. This proposal is based on the identification of a new molecule that regulates mast cell function. We believe that proposed studies will generate significant new information on the regulation of mast cell function and may offer novel therapeutic approaches for the treatment of asthma and other allergic diseases.

描述（由申请人提供）：哮喘是一种复杂的气道炎症性疾病，其特征是支气管收缩，气道高反应性和炎症。有大量证据证明了肥大细胞高亲和力IgE受体（FCERI）在哮喘发病机理中的重要作用。因此，已致力于了解该受体功能的信号传导途径。新兴的证据表明，上皮细胞衍生的细胞因子，例如白介素33（IL-33）和细菌脂多糖（LPS），通过激活其各自的受体ST2和TLR4的激活而在哮喘加剧中起着重要作用，但其作用机制仍然未知。髓样分化因子（MYD）88是最近端的衔接子分子，它均传递IL-33和LPS信号。我们对MyD88进行了新的观察，不仅调节了肥大细胞中的IL-33和LPS信号传导，还有助于抗原/Ige介导的蛋白激酶B（AKT）磷酸化和细胞因子产生。我们还发现，LPS或IL-33与抗原/IgE结合细胞因子的生成协同作用，并且在MyD88 - / - 肥大细胞中几乎消除了这种串扰。基于这些发现，我们假设MYD88通过调节和跨调节肥大细胞中的FC5RI信号传导促进过敏性炎症。提出了两个具体的目的，以进一步探索MyD88在体内的过敏性炎症的体外和鼠模型中的MyD88的作用。在AIM＃1中，我们将使用逆转录病毒以野生型或转基因修饰的MyD88转染MyD88 - / - 肥大细胞，以描绘该衔接子分子如何调节并跨桅杆细胞中的FCERI信号传导。在AIM＃2中，我们将首先检验以下假设：MyD88在肥大细胞中介导的体内介导过敏性炎症。然后，我们将调节肥大细胞中的MyD88信号传导，并确定该调节对过敏性炎症的影响。我们认为，拟议的研究将产生有关肥大细胞中FCERI信号传导调控和交叉调节的重要新信息，并可能为治疗哮喘和其他过敏性疾病的治疗提供新颖的治疗方法。公共卫生相关性：哮喘是一种复杂的气道炎症性疾病，其特征是支气管收缩，气道高反应性和炎症。据估计，大约有1700万美国人患有哮喘，其中三分之一的孩子。近年来，哮喘患病率和严重性在全球范围内一直在急剧增加。肥大细胞释放引起哮喘和其他过敏性疾病症状的炎症介质。该建议基于调节肥大细胞功能的新分子的鉴定。我们认为，拟议的研究将产生有关调节肥大细胞功能的重要新信息，并可能为治疗哮喘和其他过敏性疾病提供新颖的治疗方法。