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Isoprenoid Biology in Asthma: Proof-of-Principle and Method Development

哮喘中的类异戊二烯生物学：原理验证和方法开发

基本信息

批准号：
10015331
负责人：
Amir A. Zeki
金额：
$ 7.85万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
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：
2019-09-10 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10015331
关键词：
3-hydroxy-3-methylglutaryl-coenzyme A Acute Address Airway Resistance Alcohols Allergic Applications Grants Asthma Award Biology Blood Bronchoalveolar Lavage CCL24 gene CCL26 gene CD8B1 gene Cell Count Cell Culture Techniques Cell membrane Cells Cholesterol Chronic Coenzyme A Collagen Data Detection Development Diphosphates Disease Disease model Enzymes Eosinophilia Eotaxin Epithelial Epithelial Cells Epithelium Exposure to Extrinsic asthma Family Farnesol Fluorescence Fluorescence-Activated Cell Sorting Future Gene Silencing Goals Goblet Cells Grant Guanosine Triphosphate Phosphohydrolases Harvest High Pressure Liquid Chromatography House Dust Mite Allergens Human Hydroxymethylglutaryl-CoA Reductase Inhibitors Hyperplasia Immune In Vitro Inflammation Inhalation Inhalators Interleukin-13 Knowledge Lead Lipids Lung Mass Spectrum Analysis Measures Mediating Methods Molecular Monomeric GTP-Binding Proteins Mucous Membrane Mus Natural Killer Cells Oxidoreductase Pathogenesis Pathway interactions Pharmacology Phosphorylation Plasma Cells Play Population Post-Translational Protein Processing Production Proteins Recurrence Regulatory T-Lymphocyte Research Support Respiratory physiology Role STAT6 gene Signal Transduction Small inducible cytokine A24 Squalene Stains Sterols Structure of parenchyma of lung Suggestion Tail Techniques Technology Testing Tissues Western Blotting Work airway epithelium airway hyperresponsiveness airway inflammation airway remodeling animal tissue asthma model asthmatic biobank chemokine cytokine empowered eosinophil eosinophilic inflammation experimental study extracellular farnesyl pyrophosphate geranylgeraniol human disease human tissue in vivo inhibitor/antagonist isopentenyl pyrophosphate isoprenoid isoprenylation method development mevalonate mouse model novel persistent symptom prevent recruit response rho targeted treatment tool translation to humans

项目摘要

PROJECT SUMMARY We have discovered a role for the mevalonate (MA) pathway lipid metabolites known as isoprenoids in mediating type 2 inflammation in asthma disease models. This finding is novel and emerges from work previously accomplished in my K08 award, and establishes the MA pathway as integral to allergic eosinophilic inflammation in asthma. Our preliminary data show that excess pools of the isoprenoid molecules known as farnesylpyrophosphate (FPP) and geranylgeranyl-PP (GGPP) markedly augment interleukin-13-induced STAT6 activation and eotaxin-2 and -3 production in human airway epithelial cells in vitro, key molecular pathways in Th2/type 2 inflammation in asthma. Further, inhibition of FPP and GGPP synthesis with HMG-CoA reductase inhibitors (‘statins’), the enzyme that synthesizes MA upstream of the isoprenoids, inhibits IL-13-induced eotaxin production and extracellular secretion. The eotaxins being a major chemokine for eosinophil recruitment into airway tissues, our results suggest that high levels of airway isoprenoids mediate and promote type 2 eosinophilic airway inflammation. Furthermore, our in vivo data using mouse models of asthma, confirm the critical role of the MA pathway in mediating allergic eosinophilic inflammation. Depleting MA pharmacologically, and therefore the downstream metabolites FPP and GGPP, significantly inhibits lung and airway eosinophilia. While these data are suggestive of their role in disease pathogenesis, they are limited to human airway epithelial cell culture and mouse models of asthma. Via this R03 proposal, we wish to establish the role of isoprenoids in human disease and ultimately determine if excess levels of airway mucosal isoprenoids correlate with degree of persistent airway eosinophilic inflammation in asthma. Therefore to address this gap in knowledge, we hypothesize that excess levels of airway epithelial isoprenoids enhance type 2 eosinophilic inflammation in vivo by further inducing epithelial JAK/STAT6 phosphorylation. We will address this hypothesis via two specific aims: (1) To determine if high levels of exogenous airway isoprenoids augment eosinophilic airway inflammation in vivo. (2) To validate a quantitative method of measuring airway and lung isoprenoids using specialized mass spectrometry in pre- existing animal and human tissues. Accomplishing these goals will establish the proof-of-principle that excess isoprenoids in vivo play a role in disease pathogenesis, and most importantly, provide the tools necessary to apply this technology to human asthmatics in future grant R01 grant applications.

项目总结