G-Protein Coupled Receptor Kinase-2 on IgE Signaling in Mast Cells

G 蛋白偶联受体激酶 2 对肥大细胞中 IgE 信号传导的影响

基本信息

批准号：
8317532
负责人：
Hydar Ali
金额：
$ 24万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-15 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8317532
关键词：
ADRBK1 gene ADRBK2 gene Accounting Adult Affect Affinity Age Agonist Allergens Allergic Allergic Disease Allergic inflammation Allergic rhinitis American Anaphylaxis Antibodies Asthma Attenuated Beta-Adrenergic Receptor Kinase 1 Body Temperature Bone Marrow Bone Marrow Stem Cell Bronchoconstriction Cell Degranulation Cell physiology Cessation of life Child Complement 3a Development Disease Embryo Extrinsic asthma Food Hypersensitivity G Protein-Coupled Receptor Signaling G protein coupled receptor kinase G-Protein-Coupled Receptors GRK5 gene GRK6 gene Generations Health Care Costs Histamine Release Hospitalization Human Hypersensitivity IgE IgE Receptors Immune response In Vitro Inflammation Mediators Knock-in Mouse Lipids Lung Lung Inflammation Mediating Mediator of activation protein Modeling Mus Outcome Pathogenesis Patients Phosphorylation Play Prevalence Public Health Pulmonary Edema Regulation Research Retroviral Vector Rhinitis Role Severities Signal Pathway Signal Transduction Signaling Molecule Slice Surveys Symptoms Testing United States United States Food and Drug Administration Work airway hyperresponsiveness allergic response base cytokine desensitization disability economic cost in vivo mast cell novel novel strategies novel therapeutic intervention omalizumab overexpression receptor small hairpin RNA

项目摘要

DESCRIPTION (provided by applicant): Allergic diseases are among the major causes of illness and disability for all ages in the United States. Food allergy affects about 6% to 8% of children under the age of four, and more than 3.7% of adults in the U.S. More than 23 million people in the United States have asthma. It accounts for ~500,000 hospitalizations each year, was responsible for 3,384 deaths in 2005 and has an annual economic cost of ~$20b. Intense research over the past 30 years has increased our understanding of the pathogenesis of asthma and other allergic diseases. These diseases are caused by an overzealous Th2 immune response to allergens in which immunoglobulin E (IgE) and mast cells play critical roles. Thus, aggregation of high affinity IgE receptor (Fc5RI) by allergen on mast cells results in rapid histamine release and the generation of lipids and cytokines, which are responsible for the manifestations of allergic diseases. The focus of our research has been to study G protein coupled receptor (GPCR) signaling in mast cells. It is generally accepted that agonist-induced GPCR phosphorylation by one or more of the G protein coupled receptor kinases (GRKs) is responsible for receptor desensitization. Unexpectedly, we found that silencing GRK2 expression in human mast cells substantially inhibits Fc5RI-mediated degranulation. Based on this finding, we hypothesize that GRK2 plays a novel role in allergic diseases by promoting Fc5RI signaling in mast cells. In aim #1, we will generate murine bone marrow-derived mast cells (BMMC) with silencing or overexpression of GRK2 in vitro. In aim #2, we will use mast cell "knock-in" approach to generate mice with mast cell-specific silencing/overexpression of GRK2. Passive systemic anaphylaxis (PSA), bronchoconstriction in precision cut murine lung slices and murine model of allergic asthma will be used to test the hypothesis that mast cell-specific expression of GRK2 is required for allergic responses in vivo. If the outcome of the proposed studies are realized it may provide novel approaches for the treatment of allergic diseases such as food allergy, anaphylaxis, rhinitis and asthma.

描述（由申请人提供）：过敏性疾病是美国各年龄段疾病和残疾的主要原因之一。食物过敏影响美国约 6% 至 8% 的四岁以下儿童和超过 3.7% 的成年人。美国有超过 2300 万人患有哮喘。它每年导致约 500,000 人住院，2005 年造成 3,384 人死亡，每年造成的经济损失约为 200 亿美元。过去 30 年的深入研究增加了我们对哮喘和其他过敏性疾病发病机制的了解。这些疾病是由对过敏原过度活跃的 Th2 免疫反应引起的，其中免疫球蛋白 E (IgE) 和肥大细胞发挥着关键作用。因此，过敏原在肥大细胞上聚集高亲和力 IgE 受体（Fc5RI）会导致组胺快速释放以及脂质和细胞因子的产生，从而导致过敏性疾病的表现。我们研究的重点是研究肥大细胞中的 G 蛋白偶联受体 (GPCR) 信号传导。人们普遍认为，一种或多种 G 蛋白偶联受体激酶 (GRK) 激动剂诱导的 GPCR 磷酸化是受体脱敏的原因。出乎意料的是，我们发现沉默人肥大细胞中GRK2的表达可以显着抑制Fc5RI介导的脱颗粒。基于这一发现，我们假设 GRK2 通过促进肥大细胞中的 Fc5RI 信号传导在过敏性疾病中发挥新作用。在目标#1中，我们将在体外产生GRK2沉默或过度表达的鼠骨髓源性肥大细胞（BMMC）。在目标#2中，我们将使用肥大细胞“敲入”方法来产生肥大细胞特异性沉默/过度表达GRK2的小鼠。被动全身性过敏反应 (PSA)、精密切割的小鼠肺切片中的支气管收缩和过敏性哮喘的小鼠模型将用于检验体内过敏反应需要肥大细胞特异性表达 GRK2 的假设。如果拟议研究的结果得以实现，它可能会为治疗食物过敏、过敏反应、鼻炎和哮喘等过敏性疾病提供新方法。