The role of membrane trafficking regulation for mast cell-mediated allergic disorders

膜运输调节对肥大细胞介导的过敏性疾病的作用

• 批准号: 372803903
• 负责人: Professorin Dr. Kyeong-Hee Lee
• 金额: --
• 依托单位: Institut für Klinische Chemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/372803903?language=en
• 关键词: role; membrane; trafficking; regulation; mast

Allergies pose a serious and increasing public health problem. Critical effector functions in allergic disease are mediated by mast cells. Upon allergen-induced activation, mast cells rapidly degranulate and release a multitude of inflammatory mediators that orchestrate the allergic reaction. Granule exocytosis during mast cell activation requires a series of highly ordered and tightly regulated membrane trafficking events. Perturbation of any of these vital steps during mast cell degranulation can have severe consequences for mast cell function. Thus, there is intense interest in unraveling the cellular processes that ultimately regulate mast cell degranulation and mediator release, as it may provide novel therapeutic targets for mast cell-mediated allergic disorders. However, despite all efforts, many of the basic molecular and cellular mechanisms that regulate vesicle trafficking during mast cell degranulation are still poorly understood.Our research group intensively studies the role of membrane trafficking processes for immune cell signaling and function. To characterize novel regulatory mechanisms of mast cell degranulation and to investigate their physiological relevance for allergic/anaphylactic reactions, we here propose to study the roles of two distinct regulators of membrane trafficking, Lyst and Rin3, in mast cell biology. Preliminary work by our group already strongly indicates a critical role of these molecules in mast cells. To define the function of Lyst and Rin3 in mast cell-mediated allergic reactions, we will employ a dual strategy, in which cell biological and mechanistic in vitro studies are complemented by analysis of anaphylactic reactions in vivo utilizing Lyst- and Rin3-deficient mice. Major aims of the proposal are the characterization of the role of lysosomal trafficking regulator Lyst for mast cell granule organization/structure and its functional impact on mast cell-mediated allergic/anaphylactic reactions. Moreover, we will also perform a detailed functional and mechanistic analysis of the role of the Rab5-specific guanine nucleotide exchange factor Rin3 for mast cell mediator release and anaphylactic reactions. Together, the proposed experiments on the role of membrane trafficking regulators for mast cell function will not only provide novel insights into the complex regulatory mechanisms of mast cell degranulation, but may also reveal how perturbations in these processes can contribute to the pathophysiology of allergic disease.In addition, financial support of the project will foster a promising young scientist, Andreas Westphal, who is just finishing his PhD studies in Prof. Lees laboratory. Andreas Westphals excellent studies on the role of Lyst in innate immune cells provide the basis for the proposed studies and have earned him a first authorship on our recent publication in the Journal of Experimental Medicine (Westphal et al., JEM, 2016).

过敏是一个严重且日益严重的公共健康问题。肥大细胞介导变应性疾病中的关键效应物功能。在过敏原诱导的激活下，肥大细胞迅速脱颗粒并释放大量炎症介质，这些炎症介质协调过敏反应。肥大细胞激活过程中的颗粒胞吐需要一系列高度有序和严格调控的膜运输事件。在肥大细胞脱颗粒过程中，任何这些重要步骤的扰动都可能对肥大细胞功能产生严重后果。因此，人们对揭示最终调节肥大细胞脱颗粒和介质释放的细胞过程非常感兴趣，因为它可能为肥大细胞介导的过敏性疾病提供新的治疗靶点。然而，尽管所有的努力，在肥大细胞脱颗粒过程中调节囊泡运输的许多基本分子和细胞机制仍然知之甚少。我们的研究小组深入研究了膜运输过程在免疫细胞信号传导和功能中的作用。为了描述肥大细胞脱颗粒的新调控机制，并研究其与过敏反应的生理相关性，我们提出研究两种不同的膜运输调节因子Lyst和Rin3在肥大细胞生物学中的作用。我们小组的初步工作已经有力地表明了这些分子在肥大细胞中的关键作用。为了确定Lyst和Rin3在肥大细胞介导的过敏反应中的功能，我们将采用双重策略，在体外进行细胞生物学和机制研究的同时，利用Lyst和Rin3缺陷小鼠进行体内过敏反应分析。该提案的主要目的是表征溶酶体运输调节剂Lyst在肥大细胞颗粒组织/结构中的作用及其对肥大细胞介导的过敏/过敏反应的功能影响。此外，我们还将对rab5特异性鸟嘌呤核苷酸交换因子Rin3在肥大细胞介质释放和过敏反应中的作用进行详细的功能和机制分析。综上所述，关于细胞膜转运调节因子在肥大细胞功能中的作用的实验不仅将为肥大细胞脱颗粒的复杂调节机制提供新的见解，而且还可能揭示这些过程中的扰动如何有助于过敏性疾病的病理生理。此外，该项目的资金支持将培养一名有前途的年轻科学家Andreas Westphal，他刚刚在lee教授的实验室完成他的博士研究。Andreas Westphals对Lyst在先天免疫细胞中的作用的出色研究为我们提出的研究提供了基础，并为我们最近在《实验医学杂志》（Journal of Experimental Medicine）上发表的论文赢得了第一作者的身份（Westphal et al.， JEM, 2016）。