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Signal Transduction Pathways in Eosinophil Priming

嗜酸性粒细胞启动中的信号转导途径

基本信息

批准号：
7391415
负责人：
PAUL JOHN BERTICS
金额：
$ 38.78万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-12-01 至 2012-11-20
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7391415
关键词：
Abbreviations Adherence Affect Allergic Arrestin 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 End Point 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 Numbers 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 allergic airway inflammation arrestin3 base beta-arrestin cell motility cell type chemokine concept cytokine cytotoxic eosinophil fMet-Leu-Phe receptor in vivo methionyl-leucyl-phenylalanine migration programs proto-oncogene protein pim-1 response transcription factor

项目摘要

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.

本提案的重点是确定调节人类嗜酸性细胞关键方面的细胞机制