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Die Rolle der C/EBP-alpha isoformen und ihrer Modifikationen zur Pathologie des menschlichen Asthma

English title The contribution of C/EBP-alpha isoforms and their post-translational modification to the pathology of asthma
Applicant Roth-Chiarello Michael
Number 143360
Funding scheme Project funding (Div. I-III)
Research institution Pulmonary Cell Research Biomedicine Univeristy Hospital Basel
Institution of higher education University of Basel - BS
Main discipline Pathophysiology
Start/End 01.10.2012 - 30.09.2014
Approved amount 160'443.00
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All Disciplines (7)

Discipline
Pathophysiology
Structural Research
Cellular Biology, Cytology
Respiratory Diseases
Pharmacology, Pharmacy
Physiology : other topics
Molecular Biology

Keywords (7)

post-translational modification; cellular location; C/EBP-alpha isoforms; muscle cell diffrentiation; airway inflammation; asthma; airway remodelling

Lay Summary (English)

Lead
Lay summary

Asthma affects more than 350 million people from which the majority are children. Since thirty years, the prevalence of asthma is steadily increasing worldwide without known causes. Several studies published in 2011 and 2012 described that the available therapies for asthma are inadequate and over 50% of asthma patients are poorly controlled. All studies concluded that there is the need of better understanding the disease’s pathophysiology and to identify new therapeutic and diagnostic targets.

Beside chronic airway inflammation, airway wall remodelling is a major pathology of asthma. Recent studies in human and primates suggested that these structural changes of the airway wall can cause chronic inflammation. In 2009 we were the first to show that in asthma the protein synthesis (translation) of the cell differentiation factor C/EBP-α is disease and cell type specific in airway smooth muscle cells and is most probably the cause of airway wall muscle hypertrophy and hyperplasia. Furthermore, we reported that two well known triggers of asthma exacerbation (house dust mite allergen, cigarette smoke) reduce the translation of C/EBP-α in airway smooth muscle cells causing hyper-proliferation and secretion of inflammatory cytokines.

In total we can document the reduced expression of C/EBP-α in 63 smooth muscle samples of asthma patients suffering either from chronic or allergic asthma. In the healthy lung C/EBP-α directs lung development during embryogenesis, apoptosis and tissue repair and in other cell types it directs maturation (adipocytes, hematopoetic cells). The mechnaism how C/EBP-α controls cell differentiation is not fully understood and it is assumed that the four isoforms play a directive role. Furthermore, post-tranmslational modifications of the C/EBP-α proteins may regulate its interactionw with other transcription factors including CREB, AP-1, Oct-1, and hormone receptors. It was recently suggested that each of the four known C/EBP-α isoforms, executes specific functions which depend on the cellular compartment they are located.

In this project, we will investigate the asthma specific modified expression of C/EBP-α isoforms. In earlier experiments we used antibodies that recognised different epitopes of C/EBP-α which showed different expression ratios of the different isoforms. First, we aim to better define the cell compartmental accumulation of specific C/EBP-α isoform in isolated human diseased and healthy airway smooth muscle cells and in tissue sections of asthma patients.

Second, we will use different epitope specific antibodies to isolate the different C/EBP-α isoforms from asthmatic and non-asthmatic smooth muscle cells and then sequence the amino acids. The aim of this part is to identify possible sides for post-translational modifications including phosphorylation, sumoylation, ubiquitinylation and glutathionylation. Each of this modification can affect the cellular location and function of C/EBP-α.

Third, we aim to generate modified C/EBP-α isoform expression vectors to study their effect on smooth muscle cell differentiation by determining the expression of α-smooth muscle actin, desmin, calponin; on mitochondria activity, on proliferation and secretion of inflammatory cytokines.

The expected results will provide new understanding for the role of C/EBP-α isoforms in the physiology of the healthy lung as well as the contribution of specific isoforms to the pathology of asthma. We expect that the novel data will help to establish new concepts for therapy or even the cure for the disease.

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
PDGF-BB induces PRMT1 expression through ERK1/2 dependent STAT1 activation and regulates remodeling in primary human lung fibroblasts.
Sun Qingzhu, Liu Li, Mandal Jyotshna, Molino Antonio, Stolz Daiana, Tamm Michael, Lu Shemin, Roth Michael (2016), PDGF-BB induces PRMT1 expression through ERK1/2 dependent STAT1 activation and regulates remodeling in primary human lung fibroblasts., in Cellular signalling, 28(4), 307-15.
Specific regulation of PRMT1 expression by PIAS1 and RKIP in BEAS-2B epithelia cells and HFL-1 fibroblasts in lung inflammation.
Liu Li, Sun Qingzhu, Bao Rujuan, Roth Michael, Zhong Bo, Lan Xi, Tian Jia, He Qirui, Li Dongmin, Sun Jian, Yang Xudong, Lu Shemin (2016), Specific regulation of PRMT1 expression by PIAS1 and RKIP in BEAS-2B epithelia cells and HFL-1 fibroblasts in lung inflammation., in Scientific reports, 6, 21810-21810.
Constitutive high expression of PRMT1 in asthmatic airway smooth muscle cells is caused by reduced microRNA-19a and leads to enhanced remodeling
Sun Qingzhu, Liu Li, Wang Hui, Mandal Jyotshna, Khan Petra, Hostettler Katrin, Stolz Daiana, Tamm Michael, Molino Antonio, Lardinois Didier, Lu Shemin, Roth Michael, Constitutive high expression of PRMT1 in asthmatic airway smooth muscle cells is caused by reduced microRNA-19a and leads to enhanced remodeling, in Journal of Allergy and Clinical Immunology.

Collaboration

Group / person Country
Types of collaboration
Jiaotong University China (Asia)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
University of Naples Italy (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Dhulikel Hospital Nepal (Asia)
- in-depth/constructive exchanges on approaches, methods or results
- Exchange of personnel
National Institute of Diseases of Chest & Hospital Bangladesh (Asia)
- Exchange of personnel
Manitoba University Canada (North America)
- 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
International Conference on Allergy, Asthma and Clinical Immunology Talk given at a conference Serum IgE induced airway smooth muscle cell remodelling is independent of allergens and is prevented by omalizumab 14.09.2016 Amsterdam, Netherlands Roth-Chiarello Michael;
European Respiratory Society, International congress 2016 Talk given at a conference Reduced microRNA 19a causes constitutive high expression of PRMT1 in asthma 04.09.2016 London, Great Britain and Northern Ireland Roth-Chiarello Michael;
15th International Summer School Bönigen, University Bern Talk given at a conference Remodellong in chronic inflamamtory diseases 07.08.2016 Bönigen, Switzerland Roth-Chiarello Michael;
European Respiratory Society, Scientific Meeting Estoril 2016 Poster System biology of adrenomedulin is controlled via its cell type specific expressed receptors in the human lung 23.03.2016 Estoril, Portugal Roth-Chiarello Michael;
European Respiratory Society, Scientific Meeting Estoril 2016 Poster Irisin stimulates hyaluronic acid secretion in COPD 23.03.2016 Estoril, Portugal Roth-Chiarello Michael;
World Association for Infectious Diseases and Immunological Disorders Talk given at a conference Immunomodulation for reccurring respiratory drug infection: new insights and perspectives 19.02.2016 Milano, Italy Roth-Chiarello Michael;
European Respiratory Society, International congress 2014 Poster Accute exacerbations in COPD patients are associated with increased levels of HA and HS in BAL 06.09.2014 Munich, Germany Roth-Chiarello Michael;
European Respiratory Society, International congress 2014 Poster Secretion of Hyaluronic acid is mediated by muscarinic receptors in airway smooth muscle cells with patietns with COPD 06.09.2014 Munich, Germany Roth-Chiarello Michael;
European Respiratory Society, International congress 2014 Poster Omalizumab prevents smooth muscle growth induced by asthmatic serum 06.09.2014 Munich, Germany Roth-Chiarello Michael;
European Respiratory Society, Scientific Meeting Estoril 2014 Poster Expression and effects of adrenmedulin and its receptors in COPD and asthma derived epithelial cells 21.03.2014 Estoril, Portugal Roth-Chiarello Michael;
3rd Xijing International Respiratory Congress 2013 Talk given at a conference Remodelling in chronic inflammatory airway diseases 23.11.2013 Xi'an, China Roth-Chiarello Michael;


Knowledge transfer events



Self-organised

Title Date Place
Prevention and diagnostic of asthma and COPD in Nepal and Bangladesh 01.11.2014 University Hospital Basel, Switzerland

Awards

Title Year
Fellowship of the ERS (European Respiratory Society) 2014

Associated projects

Number Title Start Funding scheme
116022 Pathogenesis of asthma and COPD: a defect of translation control of CCAAT/enhancer binding proteins? 01.04.2007 Project funding (Div. I-III)
176248 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 01.11.2017 Project funding (Div. I-III)
130740 Deregulated translation control in Asthma: gene specific or a general feature? 01.04.2010 Project funding (Div. I-III)
105737 Differenzierung der antiproliferativen und antiinflammatorischen Signalübermittlung von Kortisol und Adrenalin in der humanen Lunge 01.10.2004 Project funding (Div. I-III)

Abstract

Asthma affects more than 300 million people from which the majority are children. Since thirty years, the prevalence of asthma is steadily increasing worldwide without known causes. Recent investigations found that the current therapies are inadequate and over 50% of asthma patients are poorly controlled. These findings indicate the need of a better understanding of the disease’s pathophysiology which will help to identify new therapeutic targets. Beside chronic airway inflammation, airway wall remodelling is the major pathology of asthma. Recent studies in human and primates suggest that these structural changes in the airway walls can lead to chronic inflammation. We were the first to show that reduced translation of the cell differentiation factor C/EBP-alpha is disease and cell type specific in airway smooth muscle cells of asthma patients and leads to hypertrophy and hyperplasia. Furthermore, we reported that two well known triggers of asthma exacerbation (house dust mite allergen, cigarette smoke) reduce the translation of C/EBP-alpha in airway smooth muscle cells causing hyper-proliferation and secretion of inflammatory cytokines. How does the C/EBP-alpha deficiency contribute to asthma pathology? In our past studies, reduced expression of C/EBP-alpha was observed in over 60 smooth muscle samples of asthma patients suffering either from chronic or allergic asthma. In cells other than smooth muscle, C/EBP-alpha is the final director of cell differentiation (adipocytes, haematopoiesis, myelopoesis), it directs lung development during embryogenesis, apoptosis and tissue repair. In addition, the function of the various C/EBP-alpha isoforms depends on its interaction with other transcription factors including CREB, AP-1, Oct-1, and hormone receptors. It was recently suggested that each of the four known C/EBP-alpha isoforms, executes specific function which depend on in which compartment they are located in the cell. In this project, we will further investigate the asthma specific modified expression of C/EBP-alpha isoforms. In earlier experiments we used antibodies that recognised different epitopes of C/EBP-alpha which clearly showed different expression ratios of the different isoforms. First, we aim to better define the cell compartmental accumulation of specific C/EBP-alpha isoform in isolated airway smooth muscle cells and in tissue sections of asthma patients compared to cells and tissue sections of healthy controls.Second, we will use different epitope specific antibodies to isolate the different C/EBP-alpha isoforms from asthmatic and non-asthmatic smooth muscle cells and then sequence the amino acids. The aim of this part of the study is to identify possible sides for post-translational modifications including phosphorylation, sumoylation, ubiquitinylation and glutathionylation. Each of this modification can affect the cellular location and function of C/EBP-alpha. Third, we aim to generate modified C/EBP-alpha isoform expression vectors to study their effect on smooth muscle cell differentiation by determining the expression of alpha smooth muscle actin, desmin, calponin; on mitochondria activity, on proliferation and secretion of inflammatory cytokines. All methods needed are established in our laboratory or will be performed by one of our collaborator (mitochondria activity: Prof. P. Berger, Bordeaux). We have the ethical approval to use bronchial biopsies of asthmatic to establish primary human cell lines after written, informed consent of each patient. On average, we start one new cell line every fortnight. Control cells from healthy volunteers are obtained through our collaboration with Prof. R. Gosens (Groningen, Netherlands). The expected results will provide new understanding for the role of C/EBP-alpha isoforms in the physiology of the healthy lung as well as the contribution of specific isoforms to the pathology of asthma. We expect that the novel data will help to establish new concepts for therapy or even the cure for the disease.
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