1. Chemotherapy and Intracellular Calcium ([Ca2+]i)
2. Modulation of membrane receptors and channels and intracellular pathways by metals and metal compounds.
3. Cellular Mechanisms of Pain Modulation
4. Principles of the Respiratory Rhythm Generation
In our lab we investigate mechanisms regulating clinical as well as toxicological relevant substances (metal ions (e.g. Pb2+, Zn2+ or Al3+), metal compounds (e.g. trimethyltin, cisplatin or arsenic), or biological active substances (e.g. capsaicin, melatonin or TNF alpha) have specific actions on (neuronal) cells: they interfere with their physiological (e.g. modulation of pain reception) or pathophysiological (apoptosis) functions.
These substances activate/deactivate proteins at the cellular membrane, the organelles or in the cytosol that are part of specific intracellular signalling pathways. Therefore our laboratory is interested in the modulation of neuronal communication as well as in their interference with calcium dependent pathways, which could result in the activation/inhibition of apoptotic cascades.
Therefore, our research focuses on different levels of the interaction of drugs or environment/clinical relevant substances with different models. Our working group is interested in the interference of the above mentioned active substances with:
- membrane proteins such as channels and ATPases, and how they modulate membrane currents and the membrane potential (e.g. resulting in a modified excitability of the neurones) (electrophysiological approach);
- intracellular calcium homeostasis particularly calcium entry or calcium release from the stores, which itself will influence the in-/efflux though the calcium channels as well as it will interfere with multiple signalling pathways (imaging and molecular approach) (see attached movie);
- the "cross modulation" of activated/deactivated membrane currents and the intracellular calcium level, to analyse in which way this will result in a modified transmitter release and/or the activation of (calcium dependent) intracellular pathways that could possibly results in an activation of apoptotic pathways (mainly molecular approach) (see figures 1, 2 and 3).
To receive meaningful results which will help to understand cellular mechanisms not only adequate techniques are needed such as electrophysiological, imaging techniques as well as molecular approaches which are all already part of our daily routine but also the combined use of these techniques has to be established e.g. parallel calcium imaging with electrophysiological recordings.
Furthermore, having discovered and understood mechanisms at the cellular side, does not necessarily answer all the questions. Whether the same actions will also occur in an intact tissue or body has to be analyzed also. While testing of some neuronal functions e.g. the long term potentiation (LTP) in brain slices is today well established we also want to prove the action of our substances in a more intact in vitro model ("working heard-brainstem" preparation). In this model we already have demonstrated that different substances influence the intact neuronal network (here the respiratory network of the preBötzinger complex located within the brain stem).
The results of the different approaches will hopefully give new answers, which will help to understand more of the cellular functions. This will give insights, how toxicological and/or clinical relevant compounds interact with the cell and the organism.
Overall I would like to answer the question under which circumstances a specific drug or chemical is (neuro-)toxic and which differences at the cellular side could make the same substance a powerful tool for clinical use (e.g. as an anti-cancer drug).