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Regulation of Allergen-Induced Airway Pathophysiology by Versican

Versican 对过敏原诱导的气道病理生理学的调节

基本信息

批准号：
10549756
负责人：
Charles Wayne Frevert
金额：
$ 76.27万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-02 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10549756
关键词：
Adhesions Agonist Allergens Anti-Inflammatory Agents Asthma Binding Biopsy Cell Culture Techniques Cell physiology Cells Characteristics Chronic Data Development Disease Environment Epithelial Cells Exposure to Extracellular Matrix Fibroblasts Functional disorder Genes Glycosaminoglycans Homeostasis House Dust Mite Allergens Human Immune response In Vitro Inflammation Inflammation Mediators Inflammatory Inflammatory Response Interferon Type I Knowledge Leukocytes Lung Lung diseases Macrophage Measures Modeling Modification Morphogenesis Mouse Strains Mus Myelogenous Myeloid Cells Organ Pathway interactions Patients Pattern recognition receptor Phenotype Poly I-C Production Property Protein Isoforms Publishing Pulmonary Inflammation Pyroglyphidae Regulation Role Sampling Side Signal Pathway Source Stromal Cells Structure TCF Transcription Factor Tamoxifen Testing Therapeutic Tissues Toll-like receptors Translating Work airway epithelium airway hyperresponsiveness airway inflammation asthmatic beta catenin chemokine extracellular immunoregulation improved outcome in vivo migration mouse model novel overexpression response restraint selective expression therapeutic development tool transcription factor versican wound healing

项目摘要

Project Summary It is now recognized that the extracellular matrix (ECM) provides a bioactive environment in lungs (and other organs) that orchestrates cellular function for tissue morphogenesis, homeostasis, wound healing, and disease. Our published work and preliminary data using airway biopsies from subjects with and without asthma, mouse models, and in vitro cell cultures show that the ECM molecule, versican (gene = Vcan), accumulates in the lower airways and is strongly correlated with inflammation and airway hyperresponsiveness (AHR). We have found that versican is synthesized in response to allergens from at least two sources: fibroblasts and macrophages and that versican has a dramatic effect on leukocyte phenotype, adhesion and migration. To better understand the mechanisms whereby versican modulates the immune response to allergens, we propose to use two novel strains of mice with conditional deficiency in versican. These include Vcan-/- mice, which have a global deletion of versican when treated with tamoxifen; and LysM/Vcan-/- mice which lack versican in myeloid cells. The Vcan-/- and LysM/Vcan-/- mice have strikingly different pulmonary inflammatory responses, as summarized by three major findings: 1) stromal cells (e.g., fibroblasts) synthesize a form of versican that promotes the development of a pro-inflammatory ECM; 2) macrophage-derived versican restrains airway inflammation, which our preliminary data suggest is conferred by the selective expression of the V3 isoform of versican by macrophages; and 3) signaling pathways regulating versican expression in fibroblasts and macrophages differ, with the WNT/β-catenin/T-cell factor (TCF) pathway regulating Vcan expression in fibroblasts and, as we recently defined, the TLR/Trif/Type I interferon (IFN) pathway in macrophages. Our preliminary and published observations underscore the importance of understanding the immunomodulatory properties of versican and are the basis for our central hypothesis that allergens such as HDM increase the production of fibroblast-derived versican forming a pro-inflammatory ECM that promotes airway inflammation and AHR leading to chronic asthmatic conditions. Conversely, macrophage- derived versican forms an anti-inflammatory ECM. This hypothesis will be tested through completion of our two aims: Aim 1. Identify the role of fibroblast- vs. macrophage-derived versican in airway inflammation and AHR caused by HDM allergen and the mechanisms regulating Vcan expression in these cells. Aim 2. Define the mechanisms by which the structural components of versican promote or restrain airway inflammation through the formation of a pro- or anti-inflammatory ECM. Understanding the contextual settings in which versican provides fine control of airway inflammation and AHR is critical for the development of therapeutic strategies for improving outcomes in patients with asthma.

项目总结