Signal Transduction Pathways in Eosinophil Priming

嗜酸性粒细胞启动中的信号转导途径

• 批准号: 7843280
• 负责人: PAUL JOHN BERTICS
• 金额: $ 38.8万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7843280
• 关键词: Abbreviations; Adherence; Affect; Allergic; Arrestins; Asthma; Attenuated; Binding; Biological; Biology; Blood; Cell Count; Cell Survival; Cell membrane; Cell surface; Cells; Characteristics; Chemotactic Factors; Chemotaxis; Cholesterol; Complex; Cytoplasmic Granules; Dependence; Development; Disease; Environment; Evaluation; Event; Exhibits; Extrinsic asthma; Family; Family member; Fibrosis; Figs - dietary; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; GTP-Binding Proteins; Gene Expression; Genes; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Human; Individual; Inflammation; Inflammatory; Interleukin-3; Interleukin-5; Investigation; Janus kinase; Leukotriene C4; Leukotriene Production; Ligands; Link; Lung; MAPK1 gene; MAPK3 gene; Mediating; Mediator of activation protein; Membrane; Membrane Microdomains; Methods; Mitogen-Activated Protein Kinases; Modeling; Molecular; Pathogenesis; Pathway interactions; Patients; Peptides; Peripheral; Positioning Attribute; Principal Investigator; Process; Production; Protein Kinase; Protein Tyrosine Kinase; Proteins; RANTES; Reagent; Receptor Signaling; Regulation; Research; Role; STAT protein; Scaffolding Protein; Signal Transduction; Signal Transduction Pathway; Signaling Molecule; Stimulus; Testing; Tissues; Work; airway inflammation; allergic airway inflammation; arrestin3; base; beta-arrestin; cell motility; cell type; chemokine; cytokine; cytotoxic; eosinophil; fMet-Leu-Phe receptor; in vivo; methionyl-leucyl-phenylalanine; migration; programs; proto-oncogene protein pim-1; response; transcription factor

This proposal is focused on defining the cellular mechanisms that regulate key aspects of human eosnophil biology, including cell sensitization (priming), chemotaxis, survival and proinflammatory/cytotoxic activities. Eosinophil recruitment and activation are characteristic of airway disorders such as allergic disease, and these cells exhibit multiple effector activities that contribute to the tissue damage and fibrosis associated with asthma. In this regard, interleukin-5 (IL-5) and related cytokines are critical for modulating eosinophil degranulation, migration, gene expression, and viability. Also, low levels of IL-5-family cytokines induce the enhanced responsiveness of eosinophils to a variety of secondary agents, such as chemoattractants. Although this priming process is important for eosinophil biology, the associated signaling events are not well understood. However, we are uniquely positioned to carefully dissect the role of specific signaling events in modulating blood and airway eosinophil function. Capabilities enabling this research include: a) Routine access to large numbers of highly purified human blood and airway eosinophils. b) Our ongoing identification of key signaling molecules mediating IL-5 and chemoattractant action in blood and airway eosinophils, e.g:, Ras, the MAP kinases (ERKs 1 and 2), the transcriptional regulators STATs 3 and 5, the beta-arrestin adaptor molecules, and the survival-associated kinase Pim-1. c) Our development of essential molecular and pharmacological methods for analyzing cytokine/chemoattractant signaling in human eosinophils. These abilities allow us to test the hypothesis that eosinophil regulation by IL-5 involves the aforementioned signaling molecules, and that their regulation is important for priming blood eosinophils to become responsive to chemoattractants. The following Aims are proposed: 1) Define the mechanisms of IL-5- mediated priming of chemoattractant-induced events in human blood eosinophils using the activation of the MAP kinases (ERK1/ ERK2) as a cellular marker. 2). Determine the biological relevance of IL-5-dependent activation of specific receptor/signaling complexes (Ras/ERK, tyrosine kinases, Deta-arrestins) and the integrity of membrane microdomains in the control of blood and airway eosinophil function. 3) Test the concept that Jak-STAT-dependent pathways are linked to IL-5-mediated regulation of human eosinophil priming and function, including Pim-1 expression,.cell survival and chemoattractant-induced responses.

这项建议的重点是确定细胞机制，调节人类嗜酸性粒细胞的关键方面， 生物学，包括细胞致敏（引发）、趋化性、存活和促炎/细胞毒性活性。 嗜酸性粒细胞的募集和活化是气道疾病如过敏性疾病的特征， 这些细胞表现出多种效应物活性， 哮喘在这方面，白细胞介素-5（IL-5）和相关的细胞因子对于调节嗜酸性粒细胞（Eos）是至关重要的。 脱粒、迁移、基因表达和活力。此外，低水平的IL-5家族细胞因子诱导了 增强嗜酸性粒细胞对多种次级药物如化学引诱剂的反应性。 虽然这种启动过程对嗜酸性粒细胞生物学很重要，但相关的信号传导事件并不清楚。 明白然而，我们处于独特的地位，可以仔细分析特定信号事件在 调节血液和气道嗜酸性粒细胞功能。使这项研究成为可能的能力包括： 获得大量高度纯化的人血和气道嗜酸性粒细胞。B）我们正在进行的鉴定 介导IL-5和血液和气道嗜酸性粒细胞中的化学引诱物作用的关键信号分子，例如： Ras、MAP激酶（ERK 1和2）、转录调节因子STAT 3和5、β-抑制蛋白 衔接分子和生存相关激酶Pim-1。c）我们开发的基本分子和 用于分析人嗜酸性粒细胞中细胞因子/化学引诱物信号传导的药理学方法。这些 这些能力使我们能够检验IL-5对嗜酸性粒细胞的调节涉及上述的假设， 信号分子，并且它们的调节对于启动血液嗜酸性粒细胞成为 对化学引诱物有反应本研究的主要目的是：1）明确IL-5的作用机制， 在人血嗜酸性粒细胞中使用激活的 MAP激酶（ERK 1/ERK 2）作为细胞标志物。2）。确定IL-5依赖性 特异性受体/信号传导复合物（Ras/ERK、酪氨酸激酶、Deta-arrestins）的激活和 在控制血液和气道嗜酸性粒细胞功能中膜微区的完整性。3)测试 Jak-STAT依赖性通路与IL-5介导的人嗜酸性粒细胞调节有关的概念 引发和功能，包括Pim-1表达，细胞存活和化学引诱剂诱导的反应。