Notch signaling-mediated functions of airway eosinophils in lung disease

Notch信号介导的气道嗜酸性粒细胞在肺部疾病中的功能

基本信息

批准号：
8207983
负责人：
Lisa Ann Spencer
金额：
$ 42.08万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-01-18 至 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8207983
关键词：
Antigen-Presenting Cells Antigens Asthma CD4 Positive T Lymphocytes Cell Survival Cells Chemotaxis Cytokine Signaling Data Development Disease Disease Progression Eosinophilia Goals Human Hypersensitivity Immune Immunity Inflammatory Interleukin-4 Investigation Laboratories Lead Leucocytic infiltrate Leukocytes Ligands Longevity Lung Lung diseases Mediating Microscopic Mus Notch Signaling Pathway Ovalbumin Pathogenesis Pathway interactions Phase Receptor Activation Research Design Research Personnel Resolution Role Shapes Signal Transduction Signal Transduction Pathway Stimulus T-Lymphocyte Tacrine airway hyperresponsiveness airway remodeling asthmatic airway base cytokine design eosinophil immunoregulation in vivo insight mouse model new therapeutic target notch protein novel public health relevance receptor response therapeutic target

项目摘要

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.

描述（由申请人提供）：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。尽管人们长期以来认识到嗜酸性粒细胞参与哮喘，但嗜酸性粒细胞在疾病发病机制中的特异性、非冗余作用一直难以捉摸。然而，几个实验室最近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，并有望通过更具体的治疗靶点重振该领域。我们的总体目标是识别并从机制上定义对哮喘的发生和恶化至关重要的嗜酸性粒细胞的效应功能。与此目标一致，该提议建立在我们的新发现之上，即成熟的人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信号传导途径，既作为信号接收“靶”细胞又作为信号发送“信号”细胞。我们的初步数据确立了我们的基本假设：Notch 信号传导是对哮喘至关重要的嗜酸性粒细胞功能的基础。我们的研究将具体调查两个假设：1）Notch 受体激活与细胞因子信号并行需要，以实现哮喘气道中嗜酸性粒细胞的完全和持续激活； 2) 嗜酸性粒细胞通过 Notch 配体介导的与 T 细胞的邻分泌相互作用促进哮喘中的 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作优势。我们的建议可能为与哮喘相关的嗜酸性粒细胞功能的机制基础提供重要的见解，并扩展到涉及嗜酸性粒细胞增多的其他肺部炎症性疾病，与开发新颖的靶向治疗方法相关。公共卫生相关性：哮喘是一种非常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，是哮喘气道中的主要细胞浸润。该提案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新型靶向治疗方法的开发。