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Research Projects

Current Research projects

 

 

I. Drug resistance in oncology

 

Retinoic acid induced effects in neuroblastoma

Contact person: Vicki Wätzig

 

Retinoic acid is included in the therapy of high-risk neuroblastoma patients to eliminate minimal residual disease by inducing differentiation. Nevertheless, the formation of resistant cells during treatment with retinoic acid occurs in many cases. We examine different neuroblastoma cell lines and their responses to retinoic acid to assess new strategies for therapeutic targets.

References: PMID: 30320919

 

microRNA mediated tyrosine kinase inhibitor resistance in leukemia cells

Contact person: Meike Kähler

We investigate putative mechanisms of TKI resistance in chronic myeloid leukemia (CML) patients, who differentially responded to imatinib independent of BCR/ABL point mutations. The aim is to identify novel pathways leading to TKI resistance through miRNA expression analysis from CML patients and in-silico target gene prediction.

Membranal ABC transporters contribute to TKI resistance through increased drug efflux. We investigate the role of miRNA interaction and epigenetic alterations in an in vitro K-562 CML model in acute and chronic resistance to imatinib and nilotinib.

Cooperation partners: Prof. Michael Kneba, Dept. Internal Medicine II, UKSH Kiel, Prof. Matthias Schwab, IKP Stuttgart,

 

References: PMID: 22241070; 24352644; 29190894

 

Identification and functional characterization of candidate cancer driver genes leading to therapy resistance in leukemia cells

Contact person: Inga Nagel

 

Resistance against tyrosine kinase inhibitors (TKIs) is an emerging problem in the therapy of leukemia (e.g. chronic myeloid leukemia (CML)) leading to therapy failure or relapse. Our aim is to get insights into TKI resistance mechanisms in leukemia by analyzing transcriptome-wide expression changes, exome-wide mutations and genome-wide DNA methylation in in vitro-cell line models. Based on this data we choose candidate cancer driver genes and analyze those using CRISPR/Cas9 gene editing and functional analyses

Cooperation partners: Prof. Ole Ammerpohl, Institute of Human genetics, University of Ulm; Prof. Christoph Kaleta, Daniele Esser, Institute of Clinical Molecular Biology Kiel; PD Dr. Eva Murga, Dr. Inga Vater, Institute of Human Genetics Kiel

 

II. Pharmacogenomics and -epigenetics

 

Phenotyp-Genotype Correlationship

Contact person: Ruwen Böhm

 

We compare different next-generation and traditional sequencing methods and of the genetic impact on the pharmacokinetics of drugs using a cocktail of five probe drugs for common drug-metabolizing enzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4).
Cooperation partners: Prof. Andre Franke, Institute of Clinical Molecular Biology, PD Dr. Stefan Oswald, Institute of Pharmacology, University of Greifswald

 

Pharmacogenetics of immunosuppressants

Contact person: Henrike Bruckmüller

 

Calcineurin inhibitors such as tacrolimus are applied as immunosuppressants in kidney transplantation, however there is a large interindividual variation of plasma concentration. In cohorts of kidney transplant patients, we investigate the role of polymorphic drug metabolizing enzymes and drug transporters applying DMET-chip, pyrosequencing and TaqMan technologies to identify the major genetic factors, contributing to tacrolimus pharmacokinetics. 

Cooperation partners: Prof. Thorsten Feldkamp, Department of Internal Medicine IV, Prof. Lutz Renders, Department of Internal Medicine, Technical University Munich

 

Genetics of Neuropathic Pain

Contact person: Henrike Bruckmüller

 

The intensity and quality of neuropathic pain varies substantially. Our aim is to determine the impact of candidate genes such as TRP channels or SIGMA receptor on neuropathic, characterized by quantitative sensory testing.

Cooperation partner: Prof. Ralf Baron, Department of Neurology, Division of NeuroIogic Pain Research and Therapy

References: PMID: 30266269; 22665484; 28817717; 30266269

 

ABC transporter gene variants and miRNA interaction

Contact Person: Oliver Bruhn

 

The expression and function of ATP binding cassette (ABC) transporters is partly affected by genetic variants miRNAs. Moreover, there is increasing evidence that length polymorphisms in the 3’-untranslated region modulate miRNA binding. So far we could demonstrate 3’-UTR lengths variants in ABCB1, ABCC1, ABCC2, ABCC3 and ABCG2, partly affecting protein expression as determined by luciferase reporter gene assays.

References: PMID: 21540293; 25162314; 26895184

 

Intestinal microRNA expression

Contact Person: Henrike Bruckmüller

 

Y-Roux bypass surgery is an increasing option to treat severe obesity. Patients often take advantage of a rapidly improved metabolic status. The celluar and molecular causses are so far only partly elucidated. We aim to determine changes on mucosal mRNA and miRNA level as well on major local metabolic pathways in the Roux limb.

Cooperation partners: Prof. Werner Siegmund, PD Dr. Stefan Oswald, Institute of Pharmacology, University of Greifswald, Prof. Kaja Ludwig, Südklinikum Rostock, PD Dr. Robert Häsler, Institute of Clinical Molecular Biology, Kiel

 

III. Herb-drug interactions

 

Echinacea

Contact person: Charles Awortwe

 

The potential of herbal medicinal products to interact with prescribed medications are reported recently at an alarming rate. Meta-analysis performed on clinical studies reported in literature by our institute showed significant pharmacokinetic interaction between E. purpurea and midazolam in healthy volunteers. Further molecular investigations are needed to understand the mechanism of such interactions. We aim to assess the role of ABC drug transporters, nuclear receptor (PXR) and microRNAs in Echinacea-drug interactions in cell models with a possibility of a further clinical study in healthy volunteers.

References: PMID: 28990842, 29363155

 

IV. Risk assessment of drugs/Pharmacovigilance

 

Open Vigil

Contact Person: Ruwen Böhm

 

U.S. American and German pharmacovigilance data are provided for signal analysis, e.g., to offer more insights on drug therapy safety issues like drug-drug-interactions and to detect new signals of adverse drug reactions or interactions. The online search engines provide guidance for clinicians in certain situations.

Cooperation partners: Prof. Klein, Institut für Informatik, CAU, Prof. Tropmann-Frick, Dept. Computer Science, Hochschule für angewandte Wissenschaften, Hamburg

Source code and further information is available at: http://openvigil.sourceforge.net/

References PMID: 22318027, 27326858

 

Digital accessibility and usability of medication data

 

Contact Person: Claudia Bulin

Medication data from both hospital patients and volunteers of clinical trials are needed for research. For digital accessibility, we thus design and implement ETL-procedures such as mapping of substance names to drug dictionaries (e.g., INN) and enrichment with different ontologies (e.g., ATC codes) to allow stratification of data and clustering of results.

Cooperation partners: Prof. Andre Franke, Institute of Clinical Molecular Biology (IKMB), CAU;; Prof. Björn Bergh, Department for Medical Informatics,Institute of Medical Informatics and Statistics (IMIS), UKSH.

 

V Clinical Studies

 

Efficacy of spironolacton in fibromyalgia (ESiF)

Contact person: Thomas Herdegen, Ruwen Böhm

 

Eudra-CT: 2014-003350-13

In this double-blind, randomized, controlled clinical trial, spironolactone is used to treat fibromyalgia.

Study protocol DRKS00008024

Reference: PMID: 29913681

Cooperation partners: Prof. Marcus Steinfath, PD Dr. Matthias Grünewald (Dept. Anesthesiology, UKSH Kiel), Matthias Fischer (Fischers Apotheke, Kiel), Riemser Pharma GmbH, Omnicell GmbH

 

An Open Label, Phase Ia/Ib Trial of the DNA-PK Inhibitor MSC2490484A in Combination with Radiotherapy in Patients with Advanced Solid Tumors

Contact person: Ruwen Böhm

 

EudraCT-Nummer: 2015-000673-12

Multicenter study (PI: Poul F. Geertsen MD, Herlev, Denmark), local cooperation partner of Prof. Dunst, Department of Radiotherapy, UKSH. 

 

Whole-brain irradiation with hippocampal sparing and dose escalation on metastases: neurocognitive testing and biological imaging (HIPPORAD)

Contact person: Ruwen Böhm

 

EudraCT-Nummer: 2015-000673-12

Multicenter study (PI: Prof. Anca Grosu, Freiburg), local cooperation partner of Prof. Dunst, Department of Radiotherapy, UKSH.