translation control; epigenetics; open reading frame; asthma; epigenetic; translation regualtion; airway smooth muscle; cell differentiation control; transcription factor interaction
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.
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.
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.
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.
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.
Miglino Nicola (2011), Calreticulin Is a Negative Regulator of Bronchial SmoothMuscle Cell Proliferation, in Journal of Allergy
, 2012(2012), 1-7.
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
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.
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
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.