Metabolomics

Topic: Metabolic biomarker identification in breast cancer

Collaboration partners:  PD Dr. T. Erbes/Prof. E. Stickeler (Aachen), Dr. Marc Hirschfeld,  Dr. S. Halbach, Prof. Dr. H. Neubauer (Düsseldorf), Prof. Dr. T. Fehm (Düsseldorf)

Description: Diseases accompanied by strong metabolic disorders, like cancer show characteristic effects on cell turnover rate, activity of modifiying enzymes, DNA/RNA modifications and thus the resulting patterns of excreted modified nucleosides in biological fluids is altered. The observed elevated levels of certain ribonucleosides in the urine of cancer patients have established their potential as possible biomarkers in a non-invasive early diagnosis and therapy surveillance system.

 

Topic: Metabolomics of clinical significant mTOR dysregulations

Collaboration partners: Prof. Dr. C. Borner, Prof. Dr. G. Walz, Prof. Dr. T. Reinheckel, Prof. T. Huber  (Hamburg)

Description: Mechanistic target of rapamycin is a major regulator of metabolism, growth and survival and its dysregulation can cause severe clinical manifestations. We investigate metabolic alterations in two socioeconomic relevant diseases, i.e. diabetic nephropathy and autosomal dominant polycystic kidney disease. In both pathologies, mTORC1 is dysregulated via the tuberous sclerosis complex axis. We use different in vitro and in vivo model systems with genetic and exogenous disease triggers.

 

Topic: Mitochondrial metabolomics:  Metabolic response to genetic modifications in yeast

Collaboration partner: Prof. Dr. N. Wiedemann

Description: The mitochondrion has been described as the power house of the cell due to its major function-adenosine triphosphate (ATP) production, accompanied by electron transport chain (ETC), tricarboxylic acid cycle (TCA), along with other biological pathways. Defects in mitochondria are linked to human diseases such as cancer, Alzheimer’s disease and diabetes. These defects can cause physiological and metabolic alterations in mitochondria as well as in cytosol. Due to the huge metabolite pool in cytosol, it is difficult to address the origin of these alterations. Therefore, it is necessary to isolate mitochondria and cytosol to find out possible compartment-specific metabolic alterations, which are helpful in understanding the molecular mechanism of mitochondrial homeostasis in response to varies genetic mutations.

 

Topic: Disturbances of Metabolic Homeostasis in Model Systems for Nephronophthisis

Collaboration partners: Prof. Dr. Gerd Walz, Dr. Vadym Budnyk

Description: Nephronophthisis is an autosomal recessive form of polycystic kidney disease and the leading cause of hereditary kidney failure in children and young adults. Nephronophthisis proteins (NPHP), such as Anks3 and Anks6, localise to the primary cilium, an important cellular sensing and signalling organelle, and lead to laterality defects and kidney failure in patients. Loss of NPHPs cause massive alterations on amino acid and nucleoside metabolism. In close collaboration with Prof. Walz, effects of NPHPs on DNA damage, proliferation as well as apoptosis were investigated to elucidate whether NPHPs are required for functional ciliary signalling and metabolic homeostasis.

 

Topic: Biochemical and metabolic analysis and characterization of the asparagine metabolism in rhabdomyosarcoma

Collaboration partner: PD Dr. S. Hettmer

Description: Oncogenic pathway activation alters key metabolic processes and enables growth and rapid production of new biomass in cancer cells. Cancer cells are dependent on certain metabolic processes, which may translate into specific vulnerabilities and open novel therapeutic opportunities. We will use a well-established in vitro/ in vivo platform of Ras-driven, murine rhabdomyosarcomas (RMS) to investigate the metabolic equilibrium of sarcoma cells and identify actionable vulnerabilities. Hettmer et al. have shown that RMS display asparagine dependency, which could be a weak point in the treatment of RMS (Hettmer et al. 2015). Therefore, we will characterize the asparagine metabolism and aim to identify new therapeutic

 

Topic: Preventing ischaemia-reperfusion injury - In vivo studies of novel molecular compounds

Collaboration partners: Prof. Dr. S. Eisenhardt, Dr. Thiele, Prof. Dr. B. Breit

Description: Pentameric C-reactive protein (pCRP), being a highly conserved pentameric protein, is a classical acute-phase protein during inflammation that acts as a precursor for the opsonizing monomeric C-reactive protein (mCRP). After transplantation, when tissue is revascularized it is prone to reperfusion which is being worsened by pCRP. After being activated by phospholipids from activated or ruptured membranes, pCRP dissociates into its monomers thus exacerbating the immune reaction. Novel compounds have been synthesized which inhibit the Phosphocholine induced dissociation and thus reduce formation of mCRP. These compounds have been tested in vitro and will be tested in vivo in Wistar Rats to determine bioavailability, pharmacokinetics and metabolism.

 

Topic: Autophagy in human keratinocytes: Metabolic Monitoring of LecB treated human keratinocytes

Collaboration partners: Prof. Dr. W. Römer, Dr. A. Landi

Description: Pseudomonas aeruginosa is a gram negative and opportunistic pathogen, Its infections results in biofilm formation. The P. aeruginosa lectin LecB has been described to subvert several processes in the host cell but its impact on cellular metabolism has not been addressed so far. Our screening reveals a dramatic impact of LecB on the amino acid and lipid metabolism. Specifically, whereas the amino acid levels are reduced, the lipid levels are increased upon treatment. As metabolism drives several essential cellular processes also during bacterial infections, investigating the metabolic host cell responses upon the bacterial lectin LecB may also provide a better understanding of skin infections and pave the way for new concepts in antibacterial therapies.

 

Topic: Identification of metabolic biomarkers of early and late recurrent pancreatic ductal adenocarcinoma

Collaboration partner: Prof. U. Wittel

Description: Pancreatic ductal adenocarcinoma (PDAC) is one of the major causes of cancer-related mortality with 5-year overall survival below 5 %. Approximately 20 % of all PDAC patients are candidates for resection, whereas about 60 % of these patients experience local or metastatic recurrence within 12 months after curative surgery. Today, disease recurrence cannot be predicted with biomarkers at all. Many studies are aiming to identify biomarkers in patient blood or urine for prediction of disease recurrence. With patient-derived organoid (PDO) cultures, PDAC of a variety of patients can be modeled in vitro and experimental findings can be correlated to the clinical course of the donating patients. With these model, current studies revealed a pivotal role of pancreatic stellate cells (PSCs) to support cancer cell metabolism and proliferation by secreting different metabolites.

 

Topic: Regulation of plant biochemical pathways to investigate central metabolism, biosynthesis of secondary metabolites, signalling and stress response

Collaboration partners: PD Dr. J. Kreuzwieser, Prof. Dr. A. Gessler (Zürich), Prof. M.-P. Laborie, Dr. H. Winter

Description: Research projects with different woody (poplar, Douglas fir) and herbaceous (Arabidopsis) model plants, carried out at the CF Metabolomics, focus on questions of molecular physiology, plant physiology and ecophysiology. In particular, physiological response to abiotic stress (drought, flooding, cold) is studied by monitoring changes in single biomarkers and/or complex metabolite patterns. Gained insights into metabolic functioning help to tackle urgent challenges like efficient biomass production for energetic use, or tree and crop response to climate change.

 

Topic: Biosynthesis and analysis of secondary metabolites from different bacterial strains and fungi as new therapeutic agents

Collaboration partners: Prof. Dr. S. Günther, Dr. R. Teufel, Prof. Dr. L. Heide (Tübingen), PD Dr. B. Gust (Tübingen)

Description: Combinatorial biosynthesis is a procedure of molecular biology in which the combination of biosynthetical genes of different origins results in the formation of new natural products. The project is focused on metabolites with antibiotic activity isolated from actinomycetes or streptomyces which contains partially sugar moieties.

 

Topic: Metabolomics to unravel molecular mechanisms involved in Parkinson's disease and Aging

Collaboration partner: Prof. Dr. S. Eimer

Description: In a high-throughput metabolomics approach (fingerprinting & profiling) the effects of different PD agents on general metabolism in the model organism C. elegans was elucidated. The key metabolic hallmarks in cell damage development and cellular defence mechanisms were examined.

 

Topic: Metabolomics of Dexamethasone application in cochlear implants

Collaboration partners: Prof Dr. B. Breit, Prof. Dr. S. Plontke (Halle), Dr. A. Liebau (Halle)

Description: Cochlear implants are hearing aids that provide a sense of sound for patients with impaired hearing. The auditory nerve innervating the cochlear is stimulated by electric signals. Though, it has been reported that due to inflammation the tissue surrounding the implant scars, thus increasing impedance and subsequently decreasing efficacy of the hearing aid. Analytics of metabolism and pharmacokinetics in regard of using different matrices have not been performed in detail. Furthermore to the best of our knowledge, no data has been collected on the influence of glucocorticoids to the cellular homeostasis of inner ear cells which will be investigated in a cellular model using House Ear Institute-Organ of Corti 1 cells (HEI-OC1) cells.