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

7.项目摘要/摘要 过敏是一种免疫系统的紊乱，发生在对过敏原致敏之后。过敏症 致敏作用能产生免疫记忆，使身体对过敏原做出快速反应 随后的过敏原挑战。在过敏反应中，肥大细胞的激活会引起几种过敏 通过预先形成的炎症介质脱颗粒而出现症状。这一过程可以通过以下方式发生 免疫球蛋白E(IgE)依赖或非依赖的途径。依赖免疫球蛋白的肥大细胞激活是经典的 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， 对IgE非依赖性肥大细胞反应的生理学相关性了解较少。与MAS相关的G 蛋白偶联受体B2(MRGPRB2)是一种肥大细胞特异性受体，可诱导肥大细胞活化 结合小阳离子分子，如化合物48/80。虽然MRGPRB2被牵连到伪装 过敏药物反应，MRGPRB2介导的肥大细胞激活的免疫学后果是 不完全具有特征的。这项建议的目的是研究不依赖IgE的肥大细胞的作用。 在过敏性敏化背景下的反应。基于化合物48/80诱导的初步数据 过敏性记忆过敏性呼吸道炎症的小鼠模型，我们假设过敏性致敏 需要MRGPRB2介导的肥大细胞激活。为了验证这一假设，我们将调查两个目标。这个 第一个目标是研究48/80介导的过敏反应对肥大细胞和MRGPRB2的依赖性 使用肥大细胞或MRGPRB2缺陷的小鼠。第二个目标是调查下游 CD11c缺陷的MAST对48/80介导的树突状细胞变态反应的影响及依赖性 细胞缺陷和MRGPRB2缺陷小鼠。总而言之，这些研究将提供对肥大细胞功能的洞察 并可能确定肥大细胞在过敏性炎症中以前未被表征的作用。除此之外，还有一个 申请人将完成一项高级课程、临床选修课和科学技能课程。 在她的顾问的密切指导下建造。本申请中详细说明的研究和培训将 让她做好准备，从事与临床相关的基础科学事业，成为一名独立的内科科学家。

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.