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

7. 项目总结/摘要 过敏是对过敏原过敏后发生的免疫系统疾病。过敏 致敏导致针对过敏原的免疫记忆，使身体能够快速做出反应 随后的过敏原挑战。在过敏反应中，肥大细胞激活会引起多种过敏反应 通过预先形成的炎症介质脱粒而产生症状。这个过程可以通过以下方式发生 免疫球蛋白 E (IgE) 依赖性或非依赖性途径。 IgE 依赖性肥大细胞激活通常是 因其在过敏记忆形成后的过敏反应中的作用而受到赞赏；然而， 不依赖 IgE 的肥大细胞反应的生理相关性尚不清楚。 MAS相关G 蛋白偶联受体 B2 (MRGPRB2) 是一种肥大细胞特异性受体，可诱导肥大细胞激活 结合小阳离子分子，例如化合物 48/80。虽然 MRGPRB2 已涉及伪 过敏性药物反应，MRGPRB2介导的肥大细胞激活的免疫学后果是 不完全表征。本提案的目的是研究不依赖 IgE 的肥大细胞的作用 过敏反应。基于化合物 48/80 诱导的初步数据 过敏性气道炎症小鼠模型中的过敏记忆，我们假设过敏致敏 需要 MRGPRB2 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 第一个目标是检查 48/80 介导的过敏致敏对肥大细胞和 MRGPRB2 的依赖性 使用缺乏肥大细胞或 MRGPRB2 的小鼠。第二个目标是调查下游 使用 CD11c 缺陷、肥大的 48/80 介导的过敏致敏对树突状细胞的影响和依赖性 细胞缺陷和 MRGPRB2 缺陷小鼠。总之，这些研究将提供对肥大细胞功能的深入了解 并可能确定肥大细胞在过敏性炎症中以前未表征的作用。除了这个 研究，申请人将完成高级课程、临床选修课和科学技能课程 在她的顾问的密切指导下建立。本申请中详述的研究和培训将 为她作为一名独立的医师科学家从事临床相关的基础科学职业做好准备。

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.