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Novel Roles of GRK2 and beta-arrestin2 on mast cell-mediated allergy and Inflammation

GRK2 和 β-arrestin2 对肥大细胞介导的过敏和炎症的新作用

基本信息

批准号：
10611941
负责人：
Hydar Ali
金额：
$ 48.51万
依托单位：
UNIVERSITY OF PENNSYLVANIA
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：
2020-05-14 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10611941
关键词：
ADRBK1 gene Actins Adaptor Signaling Protein Allergic Contact Dermatitis Allergic Disease Anaphylaxis Antigens Arr2 Asthma Atopic Dermatitis Attenuated B-Cell Lymphomas CRISPR/Cas technology Cell Aggregation Cell Degranulation Cell surface Cells Cellular biology Chemotaxis Connective Tissue Cutaneous Development Disease Environment G protein coupled receptor kinase G-Protein-Coupled Receptors Generations Hematopoietic Histamine Homeostasis Host Defense Hypersensitivity IgE IgE Receptors Immune In Vitro Inflammation Inflammatory Inflammatory Response Life Mediating Membrane Proteins Modeling Molecular Mucosa- associated lymphoid tissue lymphoma translocation protein-1 Mucous Membrane Mus Neurogenic Inflammation PRKCA gene Pain Passive Cutaneous Anaphylaxis Pathway interactions Peritoneal Phosphorylation Play Polymers Production Protein Dephosphorylation Proto-Oncogene Proteins c-akt Pruritus Pulmonary Inflammation Regulation Resistance Role Scaffolding Protein Signal Pathway Signal Transduction Skin Tissue Testing Tissues Tryptase airway hyperresponsiveness allergic response beta-arrestin chemokine chronic inflammatory disease cofilin cytokine depolymerization desensitization in vivo mast cell mutant novel novel strategies novel therapeutics polymerization protein activation protein kinase C beta receptor recruit response

项目摘要

Summary: Mast cell (MC) activation through the aggregation of cell surface IgE receptors (FcεRI) leads to life- threatening conditions such as anaphylaxis and asthma. Recent exciting development in MC biology has been the discovery that they express a novel G protein coupled receptor (GPCR) known as MRGPRX2 (mouse counterpart MrgprB2), which contributes to a growing list of conditions such as pseudoallergy, neurogenic inflammation, non-histaminergic itch, allergic contact dermatitis and atopic dermatitis. The main objective of this proposal is to modulate FcεRI and MrgprB2-mediated responses by targeting novel signaling pathways in MCs. Following their activation, most GPCRs undergo desensitization via their phosphorylation by GPCR kinases (GRKs) and the recruitment of the adapter proteins, β-arrestins (β-arrs). We made four novel observations, which provide the basis of this proposal. First, we found that unlike most GPCRs, MRGPRX2 is resistant to GRK2-mediated desensitization but it contributes to IgE-mediated MC degranulation and cytokine production. Second, β-arr2 inhibits both IgE and MrgprB2-mediated MC degranulation by modifying unknown components downstream of Ca2+ mobilization. Third, β-arr2 contributes to MC chemotaxis in vitro and allergic contact dermatitis in vivo. Fourth, the effect of β-arr2 on MC chemotaxis is associated with Ser3 dephosphorylation of the actin depolymerization factor cofilin. While activation of protein kinase Cβ (PKCβ) promotes MC degranulation, PKCα phosphorylates cofilin at Ser23 and Ser24 to increase actin polymerization, resulting in cessation of degranulation. Based on these findings, we hypothesize that GRK2 promotes IgE- mediated responses in MCs via the regulation of Syk/Akt/NF-κB signaling but β-arr2 modulates both FcεRI and MrgprB2 responses by functioning as a scaffolding protein for phosphorylation and dephosphorylation of cofilin. In aim 1, we will determine the role of GRK2 on FcεRI-mediated MC degranulation and cytokine generation in vitro and allergic response in vivo. In aim 2, we will determine the role of β-arr2 on FcεRI and MrgprB2- resposnes in vitro and inflammatory responses in vivo. Completion of this study may provide better rationale for the development of novel therapeutics for the MC-mediated disorders.

总结：肥大细胞（MC）通过细胞表面IgE受体（FcεRI）的聚集激活导致生命- 如过敏性反应和哮喘的威胁条件。MC生物学最近令人兴奋的发展是发现它们表达一种新的G蛋白偶联受体（GPCR），称为MRGPRX 2（小鼠对应物MrgprB 2），其导致越来越多的病症，例如假变态反应、神经原性变态反应、炎症、非组胺能瘙痒、过敏性接触性皮炎和特应性皮炎。的主要目标这一建议是通过靶向新的信号通路来调节FcεRI和MrgprB 2介导的反应， MC 在其活化后，大多数GPCR通过其被GPCR磷酸化而经历脱敏激酶（GRKs）和衔接蛋白β-抑制蛋白（β-arrs）的募集。我们做了四本小说这些意见为这一建议提供了基础。首先，我们发现，与大多数GPCR不同，MRGPRX 2是对GRK 2介导的脱敏有抗性，但它有助于IgE介导的MC脱粒和细胞因子生产第二，β-arr 2通过修饰未知的蛋白质来抑制IgE和MrgprB 2介导的MC脱颗粒。下游的Ca 2+动员。第三，β-arr 2参与MC体外趋化和过敏性趋化，体内接触性皮炎。第四，β-arr 2对MC趋化性的影响与Ser 3有关肌动蛋白解聚因子cofilin的去磷酸化。蛋白激酶Cβ（PKCβ）的激活促进MC脱颗粒，PKCα磷酸化cofilin的Ser 23和Ser 24以增加肌动蛋白聚合，导致脱粒停止。基于这些发现，我们假设GRK 2促进IgE- 通过调节Syk/Akt/NF-κB信号转导介导MCs的反应，但β-arr 2调节FcεRI和 MrgprB 2通过作为cofilin的磷酸化和去磷酸化的支架蛋白发挥作用来响应。在目的1中，我们将确定GRK 2在Fcε RI介导的MC脱粒和细胞因子产生中的作用，体外和体内过敏反应。在目的2中，我们将确定β-arr 2对FcεRI和MrgprB 2的作用。体外反应和体内炎症反应。完成本研究可能会提供更好的依据用于开发MC介导的疾病的新疗法。