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Deregulated translation control in Asthma: gene specific or a general feature?

English title Deregulated translation control in Asthma: gene specific or a general feature?
Applicant Roth-Chiarello Michael
Number 130740
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 Physiology : other topics
Start/End 01.04.2010 - 31.03.2013
Approved amount 280'000.00
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All Disciplines (2)

Discipline
Physiology : other topics
Molecular Biology

Keywords (9)

translation control; epigenetics; open reading frame; asthma; epigenetic; translation regualtion; airway smooth muscle; cell differentiation control; transcription factor interaction

Lay Summary (English)

Lead
Asthma, the most frequent chronic disease (> 350 million patients) is not curable. In human asthma we found faulty translation (mRNA-protein) of the cell differentiation factor C/EBP-alpha in airway smooth muscle cells, which explains the clinical well documented muscle hyperplasia. Here we investigate if the faulty translation affects only C/EBP-alpha mRNA or also other asthma relevant mRNAs. The faulty translation might be due to calreticulin overexpression a known C/EBP translation regulator.
Lay summary
The number of people suffering from asthma is increasing worldwide since 30 years and nobody knows why. Asthma affects over 300 million people and is the major cause of absence from school and work. Asthma cannot be treated, only the symptoms can be controlled by steroids, beta-agonists and other anti-inflammatory drugs. In the past decades asthma was thought to result from an activated over sensible immune system. However, the allergic reaction may indeed be a secondary pathology which develops after a change of the airway structure. The structure of asthmatic airway is changed and becomes stiffer, causing it unable to open up easily after an asthma attack where the airway muscle constricts. Interestingly, asthma was first defined as a disease of the airway muscle in 1922. New evidence suggests that this original hypothesis was correct. Inactivating airway smooth muscle by a novel therapy results a lasting improvement of symptoms and of overall life quality of asthma patients. However, this therapy is not used for treating most asthma patients as it is a major surgical procedure. Therefore, we are looking for alternatives to control the activity of airway smooth muscle in asthma. Together with our main collaborator (Prof. Black, Sydney, Australia), we have learned to isolate airway muscle cells from asthma patients and healthy volunteers with a minimal surgical methodology. With these human cells we described new pathologies which could be confirmed in patients. Here it should be noted that no asthma animal model shows the same pathologies as we know them in humans. Therefore, it is necessary and important to use human diseased cells to find out what is going wrong in the asthmatic lung. Our major findings in the past years was that human asthmatic airway muscle cells multiply faster and secrete more inflammatory proteins compared to healthy cells. We identified a missing protein (C/EBP-alpha) which controls cells maturation and this keeps the cell in a stage where they can multiply faster. This control protein is not correctly translated from its genetic information into a protein. In 2009 we described the mechanism which is responsible for not translating this particular protein. Furthermore, we found additional proteins and inflammation enhancing factors that are deregulated in asthma. In this study we aim to find out if the same mechanism that caused the down-regulation of C/EBP-alpha is responsible for the de-regulation of these other asthma related proteins. The expected results may open a new way on how to normalise the function of airway muscle cells and thereby curing asthma
Direct link to Lay Summary Last update: 23.01.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Fast beneficial systemic anti-inflammatory effects of inhaled budesonide and formoterol on circulating lymphocytes in asthma.
Rüdiger Jochen J, Gencay Mikael, Yang Jin Q, Bihl Michel, Tamm Michael, Roth Michael (2013), Fast beneficial systemic anti-inflammatory effects of inhaled budesonide and formoterol on circulating lymphocytes in asthma., in Respirology (Carlton, Vic.), 18(5), 840-7.
The Role of IgE-Receptors in IgE-Dependent Airway Smooth Muscle Cell Remodelling
Roth Michael, Zhong Jun, ZumKeller Celine, S'ng Chong Teck, Goulet Stephanie, Tamm Michael (2013), The Role of IgE-Receptors in IgE-Dependent Airway Smooth Muscle Cell Remodelling, in PLoS ONE, 8(2), e56015-e56015.
Cigarette smoke inhibits lung fibroblast proliferation by translational mechanisms
Miglino N, Roth M, Lardinois D, Sadowski C, Tamm M, Borger P (2012), Cigarette smoke inhibits lung fibroblast proliferation by translational mechanisms, in EUROPEAN RESPIRATORY JOURNAL, 39(3), 705-711.
Noncanonical WNT-5A signaling regulates TGF-β-induced extracellular matrix production by airway smooth muscle cells.
Kumawat Kuldeep, Menzen Mark H, Bos I Sophie T, Baarsma Hoeke A, Borger Pieter, Roth Michael, Tamm Michael, Halayko Andrew J, Simoons Mirjam, Prins Alita, Postma Dirkje S, Schmidt Martina, Gosens Reinoud (2012), Noncanonical WNT-5A signaling regulates TGF-β-induced extracellular matrix production by airway smooth muscle cells., in FASEB journal : official publication of the Federation of American Societies for Experimental Biolog, 27, 1631-1643.
Steroids and β2-agonists regulate hyaluronan metabolism in asthmatic airway smooth muscle cells.
Papakonstantinou Eleni, Klagas Ioannis, Karakiulakis George, Hostettler Katrin, S'ng Chong Teck, Kotoula Vassiliki, Savic Spasenija, Tamm Michael, Roth Michael (2012), Steroids and β2-agonists regulate hyaluronan metabolism in asthmatic airway smooth muscle cells., in American journal of respiratory cell and molecular biology, 47(6), 759-67.
Calreticulin Is a Negative Regulator of Bronchial SmoothMuscle Cell Proliferation
Miglino Nicola (2011), Calreticulin Is a Negative Regulator of Bronchial SmoothMuscle Cell Proliferation, in Journal of Allergy, 2012(2012), 1-7.
Constitutive high expression of protein arginine methyltransferase 1 in asthmatic airway smooth muscle cells is caused by reduced microRNA-19a expression and leads to enhanced remodelling
Sun Qingzhu, Liu Li, Wang Hui, Mandal Jotshna, Khan Petra, Hostettler Katrin, Stolz Daiana, Tamm Michael, Molino Antonio, Lardinois Didier, Lu Shemin, Roth Michael, Constitutive high expression of protein arginine methyltransferase 1 in asthmatic airway smooth muscle cells is caused by reduced microRNA-19a expression and leads to enhanced remodelling, in Journal of Allergy and Clinical Immunology.
Dimethylfumarate inhibits TNF-α induced CXCL10 secretion by airway smooth muscle via HO-1.
Seidel Petra, Hostettler Katrin, Huges Marg, Tamm Michael, Roth Michael, Dimethylfumarate inhibits TNF-α induced CXCL10 secretion by airway smooth muscle via HO-1., in European Respiratory Journal, 41(1), 195-202.
Neuronal chemorepellent Semaphorin 3E inhibits human airway smooth muscle cell proliferation and migration
Movassagh Hesam, Shan Lianyu, Halayko Andrew, Roth Michael, Tamm Michael, Chakir Jamila, Gounni Abdelilah, Neuronal chemorepellent Semaphorin 3E inhibits human airway smooth muscle cell proliferation and migration, in Jounral of Allergy and Clinical Immunology.

Collaboration

Group / person Country
Types of collaboration
Pharmacology, University of Gronningen Netherlands (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Medical School, University of Thessaloniki Greece (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
University of Manitoba Canada (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Xijing University Hospital, 4th Military Medical University China (Asia)
- in-depth/constructive exchanges on approaches, methods or results
- Exchange of personnel

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
European Respiratory Society, international congress 2011 Poster Effect of fluticasone and formoterol combination therapy on airway remodelling 24.09.2016 Amsterdam, Netherlands Tamm Michael; Zhong Jun; Roth-Chiarello Michael;
American Thoracic Society International Conference 2013 Poster Anti-fibrotic effects of nintendanib (BIBF1120) in primary human lung fibroblasts derived from patients with IPF and from non-fibrotic controls 17.05.2013 Philadelphia, United States of America Roth-Chiarello Michael; Zhong Jun; Tamm Michael;
European Respiratory Society, international congress 2012 Poster Formoterol and fluticasone reduced the deposition of pro-inflammatory collagens 01.09.2012 Vienna, Austria Zhong Jun; Tamm Michael; Roth-Chiarello Michael;
European Respiratory Society, international congress 2012 Poster Anti-fibrotic effect of nintendanib in primary human lung fibroblasts derived from IPF 01.09.2012 Vienna, Austria Roth-Chiarello Michael; Zhong Jun; Tamm Michael;
European Respiratory Society, international congress 2012 Poster IgE induced pro-inflammatory extracellular matrix composition in airway smooth muscle cells is prevented by Omalizumab 01.09.2012 Vienna, Austria Tamm Michael; Roth-Chiarello Michael; Zhong Jun;
European Respiratory Society, international congress 2012 Poster Inter-dependence of endothelin-1 and transforming growth factor on Wnt-3A expression in IPF 01.09.2012 Vienna, Austria Tamm Michael; Roth-Chiarello Michael; Zhong Jun;
European Respiratory Society, Scientific Meeting Estoril 2012 Poster Calreticulin is a negative regulator of bronchial smooth muscle cell proliferation 01.04.2012 Estoril, Portugal Miglino Nicola; Tamm Michael; Roth-Chiarello Michael;
European Respiratory Society, Scientific Meeting Estoril 2012 Poster Neovascularisation in asthma 01.04.2012 Estoril, Portugal Keglowich Laura; Roth-Chiarello Michael; Tamm Michael;
European Respiratory Society, Scientific Meeting Estoril 2012 Poster Evidence of increased pluripotent lung cells in adult human lung tissue of fibrotic lungs 30.03.2012 Estoril, Portugal Tamm Michael; Khan-Seidel Petra; Roth-Chiarello Michael;
European Respiratory Society, International congress 2011 Poster Epigenetic de-regulated translation control of C/EBP-alpha leads to increase mesothelioma cell proliferation 24.09.2011 Amsterdam, Netherlands Zhong Jun; Roth-Chiarello Michael; Miglino Nicola; Tamm Michael;
European Respiratory Society, international congress 2011 Talk given at a conference The long acting beta2-agonist formoterol re-establish the anti-proliferative effect of glucorcoticoids in asthmatic airway smooth muscle cells 24.09.2011 Amsterdam, Netherlands Tamm Michael; Roth-Chiarello Michael; Zhong Jun;
European Respiratory Society, International congress 2011 Poster Omalizumab inhibits IgE induced extracellular matrix deposition by asthmatic airway smooth muscle cells 24.09.2011 Amsterdam, Netherlands Roth-Chiarello Michael; Tamm Michael;


Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved
Erlebniswelt Gesundheit - Mustermesse Basel 2013 Performances, exhibitions (e.g. for education institutions) 14.02.2013 Basel, Switzerland Tamm Michael; Roth-Chiarello Michael;


Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions Mustermesse Basel 2013 German-speaking Switzerland 2013

Associated projects

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

Abstract

Over the past three decades, the prevalence of asthma dramatically increased, now affecting worldwide about 300 million people according to an analysis of the WHO. Although the cause of asthma is still unknown, it remains the major cause for absence from school and work; and thus is a significant health care cost factor. Today, asthma is regarded as a chronic inflammatory lung disease caused by an over-reactive im-mune response to a wide range of stimuli. Recently there is accumulating evidence this immune response may be accompanied or caused by an altered, disease specific behaviour of the airway smooth muscle cell (ASMC). In our studies on primary hu-man ASMC of asthma patients several disease-specific cellular and bio-molecular characteristics were maintained in vitro: increased secretion of pro-inflammatory cy-tokines, contracting properties, the disease-specific extracellular matrix composition, and a predisposition to proliferate faster. The latter was associated with diminished levels of the transcription/differentiation factor C/EBP-alpha. The diminished C/EBP-alpha level was due to a decreased mRNA translation initiation, and was induced by house dust mite allergen, cigarette smoke and oxidative stress by three independent mechanisms: (i) via direct interaction of calreticulin with C/EBP mRNA, (ii) indirect via PAR-2 activation, or (iii) by depletion of glutathione. Our observations provide a rationale for how several distinct environmental stimuli lead to the same pathological outcome, known as asthma. In addition to an impaired C/EBP-alpha mRNA transla-tion, we have data showing that the translation of IL-8 is also deregulated in asthma ASMC. Previously, we have proposed and provided evidence that asthma may be regarded a disease of the airways in which a deregulated translation control of gene expression in ASMC may play a pivotal role. Based on our earlier studies we now would like to as-sess to what extent the impaired regulation of mRNA translation into proteins is pre-sent in other cell types and at what molecular level it occurs. We will also link it to environmental triggers, including allergens, physical stress and oxygen radicals. In the proposed study, we will address the following questions: (i) What are the signalling pathways that lead to a de-regulated translation initiation and if this is a disease-specific defect?(ii) Is the increased expression of inflammatory cytokines (IL-4, IL-8, RANTES, and eoxtaxin) as observed in ASMC of astma patients due to the lack of C/EBP-alpha or due to more general defect related to faulty mRNA translation? (iii) Are house dust mite allergens, pollen and oxidative stress, (common asthma trig-gers) able to cause a general deregulation of mRNA translation? (iv) Is an impaired mRNA translation a specific pathology of the ASMC of asthma patients or do we also observe it in other lung cell types of the same asthma patients (fibroblasts, epithelial cells)?The expected results will not only improve the understanding of the molecular mechanism underlying asthma, it may also provide various new aspects how asthma is initiated. The data may become the basis to develop novel therapeutic curative con-cepts rather then the existing symptom controlling drugs.
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