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A clump of breast cancer cells. The blue cells are actively growing, whereas the yellow ones are in the process of dying by programmed cell death (apoptosis).
Insert: IonTrap MS4 fragmentation pathway for identification of the hypermodified nucleoside N6-methyl-N6-threonyl-carbamoyladenosine.


(Colour-enhanced scanning electron micrograph, copyright by D. McCarthy and A. Cavanagh).


1) Metabolic biomarker identification in breast cancer

 

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.

  • 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

 

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

 

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.

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

 

3) Metabolomics of clinical significant mTOR dysregulations

 

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.

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

 

4) Mitochondrial metabolomics:  Metabolic response to genetic modifications in yeast

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.

  • Collaboration partner: Prof. Dr. N. Wiedemann

 

4) Disturbances of Metabolic Homeostasis in Model Systems for Nephronophthisis

 

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.

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

 

5) Biochemical and metabolic analysis and characterization of the asparagine metabolism in rhabdomyosarcoma

 

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 targets.

  • Collaboration partner: PD Dr. S. Hettmer

 

6) Preventing ischaemia-reperfusion injury - In vivo studies of novel molecular compounds

 

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.

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

 

7) Autophagy in human keratinocytes:
Metabolic Monitoring of LecB treated human keratinocytes

 

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.

  • Collaboration partner: Prof. Dr. W. Römer, Dr. A. Landi

8) Identification of metabolic biomarkers of early and
late recurrent pancreatic ductal adenocarcinoma

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.

 

  • Collaboration Partner: Prof. U. Wittel

 


10) Biosynthesis and analysis of secondary metabolites from different bacterial strains and fungi as new therapeutic agents

 

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.

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


11) Metabolomics to unravel molecular mechanisms involved in Parkinson's disease and Aging

 

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.

  • Collaboration partners: Prof. Dr. S. Eimer

 

12) Metabolomics of Dexamethasone application in cochlear implants

 

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.

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

 

13) Analysis of Modified Nucleosides for Biomarker Discovery in Renal Cancers

 

Cancer cells have an increased RNA and DNA turnover due to their decoupling from regulatory mechanisms, controlling growth and survival. Modified nucleosides play an important role in different types of RNA and cannot be recycled and salvaged by common pathways. Therefore, they are excreted in greater amounts by tumor cells and ultimately accumulate in the urine, making them promising candidates for biomarkers. Targeted metabolomics approaches, like HPLC coupled to triple quadrupole mass spectrometry are used for identification. In this project, murine and human ccRCC models are used to identfy and characterize modified nucleosides as putative biomarkers for ccRCC. 

  • Collaboboration partners: Prof Dr. I. Frew

 

 

14) Metabolic Analysis of Cerebrospinal Fluid for the Characterization of Neurological Disorders and Neuro Inflammation

 

Cerebrospinal fluid (CSF) represents the ideal biological matrix for the analysis of neurological disorders, since it is in direct contact with the central nervous system and therefor represents its metabolism closest. Many disease-related molecules accumulate in CSF, which enables metabolomics to decipher molecular mechanisms of diseases and to discover new biomarkers for neuroinflammatory, neurodegenerative or psychological disorders.

  • Collaboboration partners: Prof Dr. B. Grimbacher