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

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介导的肥大细胞活化。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 并可能确定肥大细胞在过敏性炎症中以前未表征的作用。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 让她做好准备，作为一名独立的医生-科学家从事临床相关的基础科学职业。

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.