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Investigating the role of IgE independent mast cell responses in allergic sensitization

研究 IgE 独立肥大细胞反应在过敏致敏中的作用

基本信息

批准号：
10054649
负责人：
Alyssa Mitson-Salazar
金额：
$ 3.03万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-15 至 2022-09-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10054649
关键词：
Acute Address Adjuvant Affect Agent 48-80 Agonist Allergens Allergic Allergic Disease Allergic inflammation Antibiotics Antigens B-Lymphocytes Bacterial Antigens Basic Science Binding Bronchoconstriction Cations Cell Degranulation Cell physiology Clinical Complex Data Data Science Dendritic Cells Dendritic cell activation Dependence Disease Fluoroquinolones G-Protein-Coupled Receptors Heparin Histamine Human Hypersensitivity ITGAX gene IgE Immune System Diseases Immune response Immunologic Memory Immunologics Inflammation Mediators Ligand Binding Ligands Mediating Memory Mentorship Modeling Mus Myeloid Cells Orthologous Gene Pathogenesis Pathway interactions Pharmaceutical Preparations Pharmacology Phenotype Physicians Physiological Prevalence Prevention Process Pruritus Reaction Research Research Training Role Scientist Secretory Vesicles Signal Transduction Substance P Symptoms Testing Th2 Cells Tissues Training Vaccines Vascular Permeabilities Vasodilation Viral Antigens Work allergic airway inflammation allergic response antigen challenge base career clinically relevant cytokine draining lymph node economic cost eosinophilic inflammation experience in vivo insight mast cell mouse model mucus hypersecretion novel strategies programs receptor response skills trafficking treatment strategy uptake

项目摘要

7. Project Summary/Abstract Allergy is a disorder of the immune system that occurs following sensitization to an allergen. Allergic sensitization results in immunological memory against an allergen that enables the body to quickly respond to subsequent allergen challenges. In the allergic response, mast cell activation causes several allergic symptoms via degranulation of pre-formed inflammatory mediators. This process can occur through immunoglobulin E (IgE)-dependent or -independent pathways. IgE-dependent mast cell activation is classically appreciated for its role in the allergic response after allergic memory has developed; however, the physiological relevance of IgE-independent mast cell responses is less understood. The MAS-related G protein-coupled receptor B2 (MRGPRB2) is a mast cell-specific receptor that induces mast cell activation upon binding small cationic molecules such as compound 48/80. While MRGPRB2 has been implicated in pseudo- allergic drug reactions, the immunological consequences of MRGPRB2-mediated mast cell activation are incompletely characterized. The objective of this proposal is to study the role of IgE-independent mast cell responses in the context of allergic sensitization. Based on preliminary data that compound 48/80 induces allergic memory in a mouse model of allergic airway inflammation, we hypothesize that allergic sensitization requires MRGPRB2-mediated mast cell activation. To test this hypothesis, two aims will be investigated. The first aim will examine the dependence of 48/80-mediated allergic sensitization on mast cells and on MRGPRB2 using mice that are deficient in mast cells or MRGPRB2. The second aim will investigate the downstream effect and dependence of 48/80-mediated allergic sensitization on dendritic cells using CD11c-deficient, mast cell-deficient, and MRGPRB2-deficient mice. Together, these studies will provide insight into mast cell function and may identify a previously uncharacterized role of mast cells in allergic inflammation. Alongside this research, the applicant will complete a program of advanced coursework, clinical electives, and scientific skill building under the close mentorship of her advisor. The research and training detailed in this application will prepare her to pursue a clinically relevant basic science career as an independent physician-scientist.

7.项目总结/摘要过敏症是一种免疫系统的疾病，发生在过敏原致敏之后。过敏致敏导致对过敏原的免疫记忆，使身体能够快速响应随后的过敏原激发。在过敏反应中，肥大细胞活化引起几种过敏反应，通过预先形成的炎性介质的脱粒而引起的症状。这个过程可以通过免疫球蛋白E（IgE）依赖性或非依赖性途径。IgE依赖性肥大细胞活化是典型的由于其在过敏性记忆发展后的过敏反应中的作用而受到赞赏;然而，不依赖IgE的肥大细胞应答的生理相关性较少被理解。与MAS相关的G 蛋白偶联受体B2（MRGPRB 2）是肥大细胞特异性受体，其诱导肥大细胞活化，结合小阳离子分子如化合物48/80。虽然MRGPRB 2与假- 过敏性药物反应，MRGPRB 2介导的肥大细胞活化的免疫学后果是不完全特征化。本研究的目的是研究IgE非依赖性肥大细胞在肿瘤发生发展中的作用。在过敏性致敏的背景下的反应。基于化合物48/80诱导的初步数据，在过敏性气道炎症的小鼠模型中，我们假设过敏性致敏需要MRGPRB 2介导的肥大细胞激活。为了检验这一假设，将研究两个目标。的第一个目标是检测48/80介导的过敏性致敏对肥大细胞和MRGPRB 2的依赖性使用缺乏肥大细胞或MRGPRB 2的小鼠。第二个目标将调查下游 48/80介导过敏致敏对树突状细胞的作用和依赖性细胞缺陷型和MRGPRB 2缺陷型小鼠。总之，这些研究将提供深入了解肥大细胞功能并且可以鉴定肥大细胞在变应性炎症中的先前未表征的作用。除此之外研究，申请人将完成高级课程，临床选修课和科学技能计划在她导师的密切指导下建造。本申请中详细介绍的研究和培训将准备她追求临床相关的基础科学事业作为一个独立的医生，科学家。