title: Pulmonary microRNA profiles identify involvement of Creb1 and Sec14l3 in bronchial epithelial changes in allergic asthma.
abstract: Asthma is highly prevalent, but current therapies cannot influence the chronic course of the disease. It is thus important to understand underlying early molecular events. In this study, we aimed to use microRNAs (miRNAs) - which are critical regulators of signaling cascades - to identify so far uncharacterized asthma pathogenesis pathways. Therefore, deregulation of miRNAs was assessed in whole lungs from mice with ovalbumin (OVA)-induced allergic airway inflammation (AAI). In silico predicted target genes were confirmed in reporter assays and in house-dust-mite (HDM) induced AAI and primary human bronchial epithelial cells (NHBE) cultured at the air-liquid interface. We identified and validated the transcription factor cAMP-responsive element binding protein (Creb1) and its transcriptional co-activators (Crtc1-3) as targets of miR-17, miR-144, and miR-21. Sec14-like 3 (Sec14l3) - a putative target of Creb1 - was down-regulated in both asthma models and in NHBE cells upon IL13 treatment, while it's expression correlated with ciliated cell development and decreased along with increasing goblet cell metaplasia. Finally, we propose that Creb1/Crtc1-3 and Sec14l3 could be important for early responses of the bronchial epithelium to Th2-stimuli. This study shows that miRNA profiles can be used to identify novel targets that would be overlooked in mRNA based strategies.
authors.affiliation: Early origins of chronic lung disease, Priority Area Asthma &Allergy, Research Center Borstel, Leibniz-Center for Medicine and Biosciences, Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Borstel, Germany.|Comprehensive Pneumology Center (CPC-M), Institute of Lung Biology and Disease, Helmholtz Zentrum München and University Hospital of the Ludwig Maximilians University (LMU), Member of the German Center for Lung Research (DZL), Munich, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Bartel
authors.affiliation: Comprehensive Pneumology Center (CPC-M), Institute of Lung Biology and Disease, Helmholtz Zentrum München and University Hospital of the Ludwig Maximilians University (LMU), Member of the German Center for Lung Research (DZL), Munich, Germany.|Children's Hospital of the Ludwig Maximilians University, Munich, Germany.
authors.forename: Nikola
authors.initials: N
authors.lastname: Schulz
authors.affiliation: Center of Allergy and Environment (ZAUM), Technische Universität and Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL), Munich, Germany.
authors.forename: Francesca
authors.initials: F
authors.lastname: Alessandrini
authors.affiliation: Comprehensive Pneumology Center (CPC-M), Institute of Lung Biology and Disease, Helmholtz Zentrum München and University Hospital of the Ludwig Maximilians University (LMU), Member of the German Center for Lung Research (DZL), Munich, Germany.
authors.forename: Andrea C
authors.initials: AC
authors.lastname: Schamberger
authors.affiliation: Numares Health, Regensburg, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Pagel
authors.affiliation: Institute of Computational Biology, Helmholtz Zentrum München and Department of Mathematics, Technische Universität München, Munich, Germany.
authors.forename: Fabian J
authors.initials: FJ
authors.lastname: Theis
authors.affiliation: Comprehensive Pneumology Center (CPC-M), Institute of Lung Biology and Disease, Helmholtz Zentrum München and University Hospital of the Ludwig Maximilians University (LMU), Member of the German Center for Lung Research (DZL), Munich, Germany.|Department of Internal Medicine V, University of Munich, Munich, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Milger
authors.affiliation: Institute of Molecular Immunology, Helmholtz Zentrum München, Munich, Germany.
authors.forename: Elfriede
authors.initials: E
authors.lastname: Noessner
authors.affiliation: Telethon Kids Institute, Centre for Health Research, The University of Western Australia, Nedlands, 6009, Western Australia, Australia.|School of Paediatrics and Child Health, The University of Western Australia, Nedlands, 6009, Western Australia, Australia.|Department of Respiratory Medicine, Princess Margaret Hospital for Children, Perth, 6001, Western Australia, Australia.|Centre for Cell Therapy and Regenerative Medicine, School of Medicine and Pharmacology, The University of Western Australia, Nedlands, 6009, Western Australia, Australia.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Stick
authors.affiliation: Telethon Kids Institute, Centre for Health Research, The University of Western Australia, Nedlands, 6009, Western Australia, Australia.|School of Paediatrics and Child Health, The University of Western Australia, Nedlands, 6009, Western Australia, Australia.|Department of Respiratory Medicine, Princess Margaret Hospital for Children, Perth, 6001, Western Australia, Australia.|Centre for Cell Therapy and Regenerative Medicine, School of Medicine and Pharmacology, The University of Western Australia, Nedlands, 6009, Western Australia, Australia.
authors.forename: Anthony
authors.initials: A
authors.lastname: Kicic
authors.affiliation: Comprehensive Pneumology Center (CPC-M), Institute of Lung Biology and Disease, Helmholtz Zentrum München and University Hospital of the Ludwig Maximilians University (LMU), Member of the German Center for Lung Research (DZL), Munich, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Eickelberg
authors.affiliation: Division of Emergency Medicine, Children's National Medical Center, Washington DC, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Freishtat
authors.affiliation: Early origins of chronic lung disease, Priority Area Asthma &Allergy, Research Center Borstel, Leibniz-Center for Medicine and Biosciences, Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Borstel, Germany.|Comprehensive Pneumology Center (CPC-M), Institute of Lung Biology and Disease, Helmholtz Zentrum München and University Hospital of the Ludwig Maximilians University (LMU), Member of the German Center for Lung Research (DZL), Munich, Germany.|Children's Hospital of the Ludwig Maximilians University, Munich, Germany.|Institute for Experimental Medicine, Christian-Albrechts-Universität zu Kiel, Kiel, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Krauss-Etschmann
mesh_terms: D000818:Animals; D001249:Asthma / Q000235:genetics* / Q000473:pathology; D001980:Bronchi / Q000473:pathology*; D002352:Carrier Proteins / Q000378:metabolism*; D002454:Cell Differentiation; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D015536:Down-Regulation / Q000235:genetics; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D020869:Gene Expression Profiling; D020397:Goblet Cells / Q000473:pathology; D006801:Humans; D006967:Hypersensitivity / Q000235:genetics* / Q000473:pathology; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D018793:Interleukin-13 / Q000378:metabolism; D008679:Metaplasia; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D015203:Reproducibility of Results; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: C115163:CREB1 protein, human; D002352:Carrier Proteins; C519509:Crtc1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; C106349:FOXJ1 protein, human; D051858:Forkhead Transcription Factors; D018793:Interleukin-13; D035683:MicroRNAs; C487999:SEC14L3 protein, human; C574573:Sec14l3 protein, mouse; D014157:Transcription Factors