Project Area B - Hyperproliferative Lung and Airway Diseases
Pulmonary hypertension is a disease of the lung vasculature characterized by progressive obliteration due to dysregulated proliferation of various vascular cell types. Against this background we plan to decipher the pro-proliferative mechanisms at the level of growth factors, inflammatory cells/mediators, reactive oxygen species, modulators of the nitrogen monoxide pathway and gene regulation via microRNAs (see schematic).
Following a translational research concept we will investigate the regulation and function of new molecular target structures, test their relevance in cell culture and animal models, confirm their relevance by verification of expression in human tissue and conduct clinical studies with suitable substances. In this new application period, in addition to classical pulmonary arterial hypertension, patient collectives will include PH-entities due to chronic inflammation (interstitial lung disease (ILD) and COPD). For these entities inflammation (airways/vasculature) can be postulated as trigger factor besides hypoxia-regulated pathways. Therefore novel therapeutic approaches will include “second generation” tyrosin kinase inhibitors as well as stimulators of soluble guanylate cyclase and chemokine receptor inhibitors (e.g. CXCR2-antagonists). Moreover, inhalative PH therapy will be optimized by controlled release formulations.
Faculty members involved: Banat, Braun, Fink, Gessler, Ghofrani, Grimminger, Günther, Kummer, Morty, Müller-Ladner, Nockher, Offermanns, Preissner, Pullamsetti, Renz, Schermuly, Schmitz, Seeger, Voswinckel, Weißmann, Wilhelm, Wygrecka
- The “cancer”-hypothesis of pulmonary hypertension – a new era of anti-pumonary hypertensive therapy
- Inflammation and immune modulation – new therapeutic concepts in PH
- Reactive oxygen species and cell membrane channels: new targets for therapy of pulmonary vascular disorders
- Nitrogen monoxide (NO) – soluble guanylate cyclase – phoshodiesterase axis in experimental right heart hypertrophy
- Role of microRNAs in pulmonary hypertension
- Controlled release formulations to optimize inhalative therapy
Rampant apoptosis of alveolar type II cells (AECII) is in the focus of the pathogenetic sequence of a number of fibrotic lung diseases, idiopathic pulmonary fibrosis (IPF) among them. Accordingly, we will investigate the causes for development of endoplasmic reticulum (ER) stress, lysosomal stress and DNA damage as main triggers of increased apoptosis of the alveolar epithelium. Another focus will be on epithelial progenitor cells, their cellular origin, molecular marker profile and regenerative capacity in models of lung fibrosis and lung development below the kidney capsule. Our working hypothesis states that progenitor cells in IPF lungs have a drastically reduced regenerative capacity and that this is reflected by surrogate markers of aging at the cellular level (shortening of telomeres, ER-stress, ROS). Regarding the execution of the fibrotic response we will investigate the role of the intrinsic (alveolar) clotting system, FoxO transcription factors, and fibroblast growth factors (FGF). In addition, we will analyze which progenitor cells feed the expanding myofibroblast pool. Finally, the role of genetic changes in the fixation of the pro-fibrotic phenotype will analyzed. Overall, the outlined activities will follow a translational, therapeutically aligned approach: molecular interventions will be tested in pre-clinical studies and developed using latest technologies (e.g. in vivo imaging for apoptosis). These approaches will be integrated into current and planned clinical trials in proof-of-concept and up to phaseII/III studies.
Faculty members involved: Barreto, Bellusci, Braun, Fink, Günther, Hackstein, Herold, Lohmeyer, Markart, Matrosovich, Morty, Müller-Ladner, Preissner, Pullamsetti, Renz, Schermuly, Schmeck, Seeger, Seifart, Stainier, Voswinckel, Vogelmeier, Wilhelm, Wygrecka
- Chronic damage to the alveolar epithelium by disturbed intracellular processing of surfactant protein B and C (SFTPB and SFTPC)
- Impact of bacterial and viral infections on type II cell homeostasis
- Role of chronic epithelial damage in the development of lung fibrosis concomitant to collagenosis
- Impact of cellular senescence on regeneration / differentiation of the alveolar epithelium
- Molecular causes and cellular origin of activated myofibroblasts
- Significance of epigenetic processes in the fixation of the fibrotic phenotype
- Translation of research findings into clinical studies
Lung cancer is the most common cause of cancer death worldwide. Despite multiple progress in treatment, 5-year survival rates is only 15% dropping to <1% for patients with metastasizing lung cancer (stage IV). UGMLC has made it its business to (1) improve understanding of the cellular genesis of lung cancer, (2) to elucidate the genetic and epigenetic mechanisms in the pathogenesis of lung cancer, (3) to understand the interaction of resident and metastasizing tumor cells within the tissue specific micro-environment, (4) to investigate the changes of lung carcinoma cells in the disease process an in treatment, that lead to tumor progression and development of treatment resistance, and (5) to implement strategies for improvement of clinical treatment.
Faculty members involved: Banat, Barreto, Bauer, U., Bellusci, Braun, Bodner, Brendel, Dahm-Daphi, Dammann, Dobreva, Engenhart-Cabillic, Grimminger, Ghofrani, Günther, Herold, Krüger, Lohmeyer, Markart, Menke, Mayer E., Müller, Neubauer, Padberg, Pleschka, Preissner, Savai, Schermuly, Schmitz, Stainier, Stiewe, Vogelmeier, Voswinckel, Weißmann, Wygrecka
- The cellular genesis of lung carcinoma
- The genetic and epigenetic mechanisms in pathogenesis of lung carcinoma
- The interaction of resident and metastasizing tumor cells with the tissue specific micro-environment
- Resistance an progression: the change of lung carcinoma cells in the disease process and under treatment
- Strategies for improvement of clinical treatment and prevention