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Finished Projects

Molecular Pulmonology

Epigenetic regulation of influenza and Streptococcus pneumoniae infection

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Foto: iLung

Molecular mechanisms of severe post-influenza pneumocccal pneumonia are mostly unknown. The project analyses multiple and specific epigentic modifications induced by influenza virus infection preparing the gound for S. pneumoniae infection, and which might be suitable targets for a therapeutical strategy.

Cooperation partner: Dr. med. Andreas Ch. Hocke (M.Sc.), Charité - Universitätsmedizin Berlin

Cooperation partner’s group website and website of the BMBF-PROGRESS

Molecular characterization of macrophage phenotypes in pneumonia and asthma

Universities of Giessen and Marburg Lung Centre – Collaborative project

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Foto: iLung

Macrophages display a broad phenotypical plasticity: they are key players in host defense toward invading pathogens and in the pathogenesis of chronic inflammatory diseases (e.g. allergic asthma), but may also display anti-inflammatory and epithelial-protective potential in these conditions. The extremes of this functional spectrum were termed “classically activated” macrophages (M1), and “alternatively activated” macrophages (M2). Manipulation of macrophage phenotypes has been identified as a putative therapeutic intervention strategy in inflammation and tumorigenesis.

Own preliminary results point to distinct chromatin and microRNA profiles of “classical” versus “alternative” phenotypes. Identification of chromatin and microRNA phenotypes can pave the way to a molecular definition and understanding of these cells, and, in addition, open up the door to a targeted manipulation as part of novel therapeutical strategies.

Cooperation partner: Priv.-Doz. Dr. rer. nat. Holger Garn, Philipps-University Marburg

Website and website of the Universities of Giessen and Marburg Lung Centre

Molecular regulation of iNOS in experimental and clinical emphysema

Universities of Giessen and Marburg Lung Centre – Collaborative project

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Foto: iLung

COPD-related emphysema and pulmonary hypertension (PH) are important clinical challenges worldwide. The underlying pathways are, however, not deciphered yet and there is no curative therapy for COPD available. In a murine smoke exposure model, vascular remodeling precedes emphysema development. Both pathologies were dependent on iNOS function. Similar regulatory and structural alterations as seen in mouse lungs were found in human COPD.

Experiments have shown that smoke exposure of human alveolar epithelial cells changed the expression of microRNAs – small non-protein coding RNAs that affect protein expression in a complex manner. Identification of microRNA and chromatin regulation in smoke-induced emphysema and vascular remodeling can pave the way to a molecular understanding, and open up the door to novel therapeutical strategies.

We will test the hypothesis, that chromatin-status and miRNA-patterns are important regulators of (1) iNOS expression and (2) the subsequent development of emphysema and vascular remodeling in cigarette smoke induced lung disease. In detail, we will determine a comprehensive miRNA and mRNA pattern, and chromatin modifications at smoke-regulated genes in alvelolar epithelial cells, endothelial cells and vascular smooth muscle cells at different time points in our murine model of chronic cigarette smoke exposure.

Cooperation partner: Prof. Dr. Norbert Weissmann, Justus-Liebig-University Giessen

Prof. Dr. Norbert Weissmann’s website at UKGM and website of the Universities of Giessen and Marburg Lung Centre

 

Extracellular Ribonuclease1: A new protective factor for vascular diseases

Recently, vascular Ribonuklease1 (RNase1) was characterized as a new, vessel-protective protein. It neutralizes or prohibits the procoagulant, oedema-promoting or hyper-inflammatory activities  of extra-cellular RNA (eRNA) within the vessel system. In this project, regulatory mechanisms of RNase-expression and –secretion as well as its protective role in vessel diseases will be determined and further validated in animal models. In addition, in patient cohorts, we will investigate whether an RNase1-deficiency or –mutant can be presumed as a risk factor for the development of hyperinflammatory or thrombotic diseases.

Cooperation Partner: Prof. Dr. Klaus T. Preissner, Biochemisches Institut, Justus-Liebig-Universität Gießen

The project is funded by the von-Behring-Röntgen-Stiftung.

Clinical Research

Peripheral blood monocyte miRNA expression in severe lung infections

International Research Training Group 1673 Berlin-Hyderabad

Functional and Molecular Infection Epidemiology

microRNAs (miRNAs) are small non protein-coding RNAs regulating the expression of gene groups on the (post-)transcriptional level. In vitro and animal studies indicate that miRNAs may be important regulators of gene expression in the immune response. Several reports demonstrated frequent genetic variations in miRNA sequences . However, the functional impact of their expression and single nucleotide polymorphisms (SNPs) is unknown in infectious lung diseases. Own unpublished data showed that bacteria causing pneumonia modulate the expression of miRNAs (e.g. miR-146a) in human peripheral blood monocytes (PBM). We hypothesise that human lung infection results in altered expression of miRNAs detectable in PBM, providing appealing targets as biomarkers. We endeavour to decipher the expression of miRNAs in PBM of patients suffering from acute bacterial pneumonia (CAP)and chronic tuberculosis (tbc) lung infection, which are important both in India and Germany. For both diseases, well characterized patients, each in India and Germany, the expression of miRNAs will be analysed , validated and compared. Function of selected miRNA in the immune reaction of PBM will be tested using artificial mimetics/antagonists. Selected known/predicted miRNA SNPs will be detected by established assays. This is the first step for the identification of new biomarkers, and the identification of important regulatory miRNAs. It will pave the way for analysis of miRNA SNP frequency and functional consequence in large patient cohorts.

Website of the IRTG 1673

 

miRNA in exhaled breath condensate as a biomarker for pulmonary diseases (PneumiR)

University Medical Center Giessen and Marburg – Collaborative project

Infections and neoplasia of the respiratory tract belong to the most frequent causes of illness and death worldwide and cause high socio-economic burden. The simple access to exhaled breath condensate (EBC) is a unique opportunity to carry out non-invasive diagnostics with high compartiment specificity. In this project, we search for small RNAs in breath condensate from patients with infections and malignancies and validate them as biomarkers.

In exhaled breath condensate of patients and healthy volunteers, we first analyze small RNAs quantitatively with the help of qPCR arrays. Afterwards, we  validate them with single assays in EBCs and other patient material.

Cooperation partner: Prof. Dr. Konstantin Meyer, Justus Liebig University, Giessen

Prof. Dr. Konstantin Meyer's website at UKGM and website of the UKGM

 

The influence of the virulence factor pneumolysin on histone modifications in pneumococcal pneumonia

Principal investigator: Dr. Kerstin Seidel

Pneumococcal pneumonia belongs to the leading causes of death worldwide. Its course is mainly determined by virulence factors of the bacterium Streptococcus pneumoniae (S. pneumoniae) and the immune response of the host, ermerging from the bronchial epithelium of the lung. In animal models of severe infections, „epigenetic“ therapeutical strategies have been studied successfully. The aim of the proposed project is providing the scientific basis for better understanding of such therapy. Therefore histone modifications within pneumococcal infection, its underlying mechanisms and impacts is to investigate.

The project is funded by the foundation P.E. Kempkes.

 

TransMIT-Project Division for translational lung research

We are part of TransMIT - Society for Technology Transfer GmbH.

Business activities

  • Experimental and translational research in the field of lung, infection and inflammation diseases

  • Analysis and functional research of signal transduction pathways, microRNAs and chromatin modifications/epigenetic regulation

  • Identification and validation of therapeutically and diagnostically relevant target proteins, proof of concept and proof of target studies

  • Establishment of models for inflammation and lung diseases (Cell culture, tissue culture, genetically defined animal models)

  • Expert evaluation and discussion of collected data

  • Scientific advice, advanced training

Target groups

  • Biotechnology and Pharmacy

  • Universities and other research institutes

If you are interested in working with us, please visit the TransMIT-website

Systems Medicine

microRNA at the crossroad of lung inflammation, regeneration and cancer (miRSys)

BMBF e:Bio - Innovationswettbewerb Systembiologie (2013-2015)

The aim of the project is to investigate the role of miRNA regulation in signalling and gene regulatory networks related to lung inflammation using an iterative approach of mathematical modelling, bioinformatics, and laboratory experiments. The project is to detect critical miRNAs for lung inflammation in pathological conditions associated to infection and cancer. Other objectives of the project are the development of bioinformatics methods for analysis and construction of miRNA related biochemical networks. The aim of this project is to develop a new workflow, based on the integration of quantitative data via mathematical modelling, to investigate the role of miRNAs in the regulation of lung inflammation, regeneration, and cancer. This strategy will be extremely valuable to propose therapeutic strategies to measure and assess the importance of miRNAs in the fate of inflammatory processes in the lung. Here, lung inflammation is proposed as an ideal case study to develop methods and techniques for application to other inflammatory pathologies.

Cooperation partner: Prof. Dr. Julio Vera-González, Dermatology Clinics, University of Erlangen

Cooperation partner’s website and website of e:Bio

 

Systems biology of lung inflammation

BMBF Forsys Partner Research Group (2008-2013)

FORSYS Logo
Foto: iLung

Two major projects will help to lay a solid basis for novel strategies of pulmonary translational medicine and provide expert knowledge and experimental standards for further mechanistic projects in applied systems biology:

Project A: Mechanistic analysis and modelling of IL-6 expression

Interleukin 6 (IL-6) is an attractive target for patient-focused systems biology modelling as it modulates pulmonary immunology in infection (e.g. pneumonia), autoimmune disease (e.g. bronchial asthma) and malignancies. It is used as important clinical biomarker of inflammation. We will build a predictive model of receptor-induced IL-6 expression in human lung epithelial cells under experimental conditions of pneumonia and asthma by iterative application of standardized and cohesive experimental examination and application of adequate mathematical modelling procedures.

Project B: Chromatin Mapping analysis and modelling of pulmonary gene expression

Signal transduction and gene expression are thought to be modular. In the second project we try to characterize and understand dynamic genome-wide modules of inflammatory gene expression in lung epithelium. Therefore, based on experience from the first project, human lung epithelial cells will be analyzed under experimental conditions of pneumonia and asthma by transcriptome analysis and chromatin immunoprecipitation on DNA-array (ChIP-Chip) on a whole genome promoter level. This complements different projects that focus on static whole-body epigenome maps and may lead to the identification of strategically promising biomarkers and drug targets in lung inflammation.

Website of the Forsys Partner Network

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