Notch signaling-mediated functions of airway eosinophils in lung disease

描述(申请人提供)：嗜酸性粒细胞是与哮喘、过敏和其他疾病相关的先天免疫白细胞。尽管嗜酸性粒细胞参与哮喘的认识由来已久，但嗜酸性粒细胞在疾病发病机制中的特定的、非多余的作用一直难以捉摸。然而，最近几个实验室的研究揭示了嗜酸性粒细胞在免疫调节和气道重塑中的新功能，改变了疾病发病机制的经典范式，并通过承诺更具体的治疗靶点来重振该领域。我们的总体目标是识别和机械地定义嗜酸性粒细胞在哮喘的启动和加重中至关重要的效应功能。与这一目标一致，这一建议建立在我们的新发现基础上，即成熟的人类嗜酸性粒细胞表达功能齐全的Notch配体和受体，表明嗜酸性粒细胞利用Notch信号通路，既作为信号接收“靶细胞”，也作为信号发送“信号”细胞。我们的初步数据确立了我们的假设，即Notch信号是嗜酸性粒细胞功能的基础，对哮喘至关重要。我们的研究将具体探讨两个假设：1)Notch受体的激活需要与细胞因子信号并行，以实现哮喘呼吸道中嗜酸性粒细胞的全面和持续激活；以及2)嗜酸性粒细胞通过Notch配体介导的T细胞旁分泌作用促进哮喘的Th2环境。虽然实验方法主要利用人类嗜酸性粒细胞，但拟议的研究也充分利用了小鼠模型的操纵优势。我们的建议可能会为与哮喘相关的嗜酸性粒细胞功能的机制基础以及与嗜酸性粒细胞增多症相关的其他肺部炎症性疾病提供重要的见解，与开发新的、有针对性的治疗方法相关。 与公共卫生相关：哮喘是一种高度流行且代价高昂的疾病。嗜酸性粒细胞是与哮喘、过敏和其他疾病相关的先天免疫白细胞，是哮喘呼吸道的主要细胞浸润。这项建议旨在阐明嗜酸性粒细胞功能导致哮喘恶化的机制基础。这些研究可能会导致开发新的、有针对性的治疗方法。

DESCRIPTION (provided by applicant): Eosinophils are innate immune leukocytes associated with asthma, allergies and other diseases. Despite the long recognition of eosinophilic involvement in asthma, specific, non-redundant roles for eosinophils in disease pathogenesis had been elusive. However, recent studies from several laboratories have revealed new functions of eosinophils in immunomodulation and airway remodeling, changing the classic paradigm of disease pathogenesis and reinvigorating the field with a promise of more specific therapeutic targets. Our overall goal is to identify and mechanistically define effector functions of eosinophils vital to the initiation and exacerbation of asthma. In line with this goal, this proposal builds upon our novel discovery that mature human eosinophils express fully functional Notch ligands and receptors, indicating eosinophils utilize Notch signaling pathways, both as signal-receiving "target" cells and as signal- sending "signaling" cells. Our preliminary data establishes our overlying hypothesis that Notch signaling underlies eosinophil functions critical to asthma. Our studies will specifically investigate two hypotheses: 1) Notch receptor activation is required in parallel with cytokine signals to achieve full and sustained activation of eosinophils in asthmatic airways; and 2) Eosinophils promote a Th2 milieu in asthma by Notch ligand-mediated juxtacrine interactions with T cells. While experimental approaches utilize predominantly human eosinophils, proposed studies also take full advantage of the manipulative benefits of mouse models. Our proposal may provide vital insights into the mechanistic basis for eosinophil functions pertinent to asthma, and by extension other inflammatory diseases of the lung involving eosinophilia, relevant to development of novel, targeted therapeutic approaches. PUBLIC HEALTH RELEVANCE: Asthma is a highly prevalent and costly disease. Eosinophils, innate immune leukocytes associated with asthma, allergies and other diseases, are the predominant cellular infiltrate in asthmatic airways. This proposal is designed to elucidate the mechanistic basis of eosinophil functions leading to asthma exacerbation. These studies may lead to the development of novel, targeted therapeutic approaches.