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The ratio of C/EBP-a to C/EBP-ß controls airway wall remodelling in asthma through the regulation of microRNA-17-92 cluster, PRMT1 and mitochondria in airway smooth muscle cells

English title The ratio of C/EBP-a to C/EBP-ß controls airway wall remodelling in asthma through the regulation of microRNA-17-92 cluster, PRMT1 and mitochondria in airway smooth muscle cells
Applicant Roth-Chiarello Michael
Number 176248
Funding scheme Project funding (Div. I-III)
Research institution Klinik für Pneumologie Medizinische Universitätsklinik Universitätsspital Basel
Institution of higher education University of Basel - BS
Main discipline Physiology : other topics
Start/End 01.11.2017 - 31.10.2019
Approved amount 316'000.00
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All Disciplines (2)

Discipline
Physiology : other topics
Pathophysiology

Keywords (6)

PRMT1; C/EBPs; Airway wall remodelling; regulation of microRNA cluster 17-92; Mitochondria; Asthma

Lay Summary (German)

Lead
Das Verhältnis von C/EBP-a zu C/EBP-ß kontrolliert Bronchialwandstrukturumbildung durch das MicroRNA cluster 17-92, PRMT1 und Mitochondrien in Bronchialwandmuskelzellen.
Lay summary

Weltweit erkranken immer mehr Menschen an Asthma, der Grund hierfür ist unbekannt. Die WHO hat berechnet, dass sich die Zahl der Asthmapatienten in 10 Jahren verdoppelt.

Charakteristisch für Asthma sind die chronische Entzündung der Bronchien und die Umbildung der Bronchialwand. Während die chronische Entzündung gut mit verfügbaren Medikamenten kontrolliert werden kann, ist die Bronchialwandumbildung nicht behandelbar. Die amerikanische Gesellschaft für Lungenheilkunde (ATS) hat 2016 angekündigt, dass ohne Behandlungserfolg bei der Bronchialwandumbildung Asthma nicht heilbar sein wird; hierfür muss man deren Ursache verstehen. Bronchialwandumbildung ist das Ergebnis mehrerer krankhafter Vorgänge: Fehlfunktion des Epitheliums, vermehrte Zahl und Grösse der sub-epithelialen Bindegewebs-und Muskelzellen, erhöhte Aktivität deren Mitochondrien und erhöhte Produktion von extrazellulärer Matrix.

In den vergangenen Jahren haben mehrere Studien gezeigt, dass die Bronchialwandumbildung durch die Fehlregulation von Zelldifferenzierungsfaktoren bedingt ist. Kürzlich konnten wir in einem Tiermodel und an Asthmapatienten wie die Fehlregulation der Zelldifferenzierung durch das Fehlen von C/EBP-α verursacht wird. Wenn kein C/EBP-α vorhanden ist, kann C/EBP-β vermehrt an das Gen für MicroRNA cluster 17-92 binden und dessen Aktivierung unterdrücken. Hierdurch wird das Protein Erk1/2 vermehrt gebildet und aktiviert. Dieser Vorgang führt zur Aktivierung von PRMT1 und Mitochondrien.

In diesen Projekt untersuchen wir die Details dieses Prozesses um neue Ansätze für die Behandlung der Bronchialumbildung beim Asthma zu finden.
Direct link to Lay Summary Last update: 11.10.2017

Responsible applicant and co-applicants

Employees

Publications

Publication
Bronchial thermoplasty decreases airway remodelling by blocking epithelium-derived heat shock protein-60 secretion and protein arginine methyltransferase-1 in fibroblasts
Sun Qingzhu, Fang Lei, Roth Michael, Tang Xuemei, Papakonstantinou Eleni, Zhai Weiqi, Louis Renaud, Heinen Vincent, Schleich Florence N., Lu Shemin, Savic Spasenjia, Tamm Michael, Stolz Daiana (2019), Bronchial thermoplasty decreases airway remodelling by blocking epithelium-derived heat shock protein-60 secretion and protein arginine methyltransferase-1 in fibroblasts, in European Respiratory Journal, 54(6), 1900300-1900300.
microRNA‐23a contributes to asthma by targeting BCL2 in airway epithelial cells and CXCL12 in fibroblasts
Jin Ai, Bao Rujuan, Roth Michael, Liu Li, Yang Xudong, Tang Xuemei, Yang Xiaojun, Sun Qingzhu, Lu Shemin (2019), microRNA‐23a contributes to asthma by targeting BCL2 in airway epithelial cells and CXCL12 in fibroblasts, in Journal of Cellular Physiology, jcp.28718-jcp.28718.
IgE Downregulates PTEN through MicroRNA-21-5p and Stimulates Airway Smooth Muscle Cell Remodeling
Fang Lei, Wang Xinggang, Sun Qingzhu, Papakonstantinou Eleni, S’ng Chongteck, Tamm Michael, Stolz Daiana, Roth Michael (2019), IgE Downregulates PTEN through MicroRNA-21-5p and Stimulates Airway Smooth Muscle Cell Remodeling, in International Journal of Molecular Sciences, 20(4), 875-875.
TGF-β Upregulated Mitochondria Mass through the SMAD2/3→C/EBPβ→PRMT1 Signal Pathway in Primary Human Lung Fibroblasts
Sun Qingzhu, Fang Lei, Tang Xuemei, Lu Shemin, Tamm Michael, Stolz Daiana, Roth Michael (2018), TGF-β Upregulated Mitochondria Mass through the SMAD2/3→C/EBPβ→PRMT1 Signal Pathway in Primary Human Lung Fibroblasts, in The Journal of Immunology, 202(1), 37-47.

Collaboration

Group / person Country
Types of collaboration
Prof S. Lu, Xi’an Jiaotong University, Xi’an China (Asia)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Porf. B Ryffel, CNRS, UMR7355, Orleans France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof Q. Sun, College of Animal Science and Technology, Northwest A&F University, Yangling 712100, Sh China (Asia)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Dr. Ch Lambers, Thorax Surgery, University Hospital Vienna Austria (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
The Annual Meeting of the Italian Respiratory Society Talk given at a conference New cellular pathologies in Asthma and COPD : new targets for therapies 11.10.2019 Ischia, Italy Tamm Michael; Stolz Daiana; Fang Lei; Roth-Chiarello Michael;
European Respiratory Society meeting 2019 Talk given at a conference Pathophysiology of and clinical insights into severe non-allergic asthma 01.10.2019 Madrid, Spain Stolz Daiana; Roth-Chiarello Michael; Tamm Michael; Fang Lei;


Communication with the public

Communication Title Media Place Year
Media relations: print media, online media Developing innovative therapies to treat asthma Open Access Government International 2018
Media relations: print media, online media Do we know the cause of asthma and COPD? Open Access Government International 2018
Media relations: print media, online media Where are the new asthma drugs? Open Access Government International 2018
Media relations: print media, online media New concepts for the pathogenesis and asthma therapy Open Access Government International 2017
Media relations: print media, online media Pneumology & Pulmonary Cell Research Open Access Government International 2017
Media relations: print media, online media Pre-disposition to chronic inflammatory lung diseases Open Access Government International 2017
Media relations: print media, online media Pulmonary Cell Research Open Access Government International 2017

Associated projects

Number Title Start Funding scheme
130740 Deregulated translation control in Asthma: gene specific or a general feature? 01.04.2010 Project funding (Div. I-III)
143360 Die Rolle der C/EBP-alpha isoformen und ihrer Modifikationen zur Pathologie des menschlichen Asthma 01.10.2012 Project funding (Div. I-III)

Abstract

The prevalence of asthma is continuously increasing worldwide as announced on the 6th March 2017 by the World Health Organization and in the State of Global Air 2017 Report (Health Effect Institute Boston, USA). The latter report points out that majority of people lives in polluted air which causes re-occurring episodes of lung inflammation and can lead to asthma. In 2016, The EU Symposium on the Awareness of Allergy declared that: “chronic airway diseases are a major and growing health problem in Europe”.Asthma is the most prevalent chronic airway disease affecting 8 % of the world’s population and the number of patient doubles every 10 years. Despite being a heterogeneous disease, the major pathologies are chronic airway inflammation and airway wall remodeling. In most patients inflammation can be well controlled by anti-inflammatory drugs, but airway wall thickening cannot be reduced by any available drug. Today, only bronchial thermoplasty in severe asthma showed lasting symptom relief after reducing airway wall thickness by destroying sub-epithelial mesenchymal cells. Therefore, leading experts in the field recently suggested that unless the mechanism driving airway wall remodeling is better understood, there will be no cure for asthma. Airway wall remodeling includes: (a) dysfunction of the bronchial epithelium, (b) hypertrophy / hyperplasia of sub-epithelial mesenchymal cells, (d) increased mitochondrial activity, and (d) increased deposition of sub-epithelial extracellular matrix. New clinical studies showed that sub-epithelial mesenchymal cells release pro-inflammatory cytokines that recruit immune cells into the airways. We and others demonstrated that remodeling of human asthmatic airway smooth muscle cells and fibroblasts is due to increased Erk1/2 MAP kinase activity, PRMT1 expression and mitochondrial mass, which are the consequence of reduced C/EBP-a expression and low levels of microRNA-19a.These studies were performed in cells isolated from more than 150 asthma patients which were collected at six hospitals from Switzerland (Basel), Italy (Naples), Belgium (Liege), Canada (Manitoba), and Australia (Sydney: Royal Prince Alfred Hospital, Royal North Shore Hospital).Referring to our earlier studies, we aim to prove that the expression of microRNA cluster 17-92 members is controlled by the ratio of C/EBP-a to C/EBP-ß. We hypothesize that the earlier reported low level of C/EBP-a in asthmatic smooth muscle cells increases the binding of C/EBP-ß to the microRNA cluster 17-92 promoter and leads to remodeling. This hypothesis will be tested in tissue sections and in isolated, diseased versus non-diseased human airway smooth muscle cells and fibroblasts. We will assess: 1) the functional link of the C/EBP-a to C/EBP-ß ratio on the expression of microRNA cluster 17-92 members. 2) the mechanism by which how C/EBP-a and -ß regulate the microRNA cluster 17-92 promoter activity by electrophoretic DNA mobility shift assay, DNA-protein precipitation assay, and luciferase reporter construct. 3) the consequence of C/EBP-a and/or C/EBP-ß knock-out in airway cells on microRNA cluster 17-92 control of Erk1/2 MAPK activity, STAT1 activity and PRMT1 expression; and 4) on mitochondria mass, mitochondrial activity, cell proliferation and extra cellular matrix deposition which all indicate remodeling. We are aware that other microRNAs had been linked to asthma, but most of those studies were focused on immune cell biology rather than on airway wall remodeling.We are confident that this study will provide new insight into the cause of airway wall remodeling in asthma and thus, provide the basis to develop new curative therapeutic strategies.
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