Research

The members of the department perform basic research but the investigations are also related to disease. Different areas are the focus of the research:

(1) Oxygen-dependent gene regulation is depending mainly on a cytosolic protein (hypoxia-inducible factor, HIF), which translocates to the nucleus and exerts its biological function by modifying gene transcription (transcription factor). The cytosolic levels of HIF itself are not only depening on its synthesis but also on its degradation, which is modulated by oxygen availability as well as by posttranslational modifications of the HIF protein. Moreover, the relation between oxygen and cytosolic HIF protein levels is also modulated by inflammation and the interactions of these parameters are studied in cell culture and other models. The studies are focussed to establish how biological oxygen sensors function and how they can be manipulated on a pharmacological or genetic basis. They are aimed to develop new strategies in supporting wound healing and in the treatment of solid tumors.

(2) The molecular regulation of oxygen homeostasis and cellular adaptation is modulated by the transport of proteins through the nuclear membrane which seems to exert a regulatory function. This is specifically true for the transcription factors involved (e.g. hypoxia-inducieble factor, HIF) but also for the molecular oxygen sensors (prolyl hydroxylases), which have to be shuttled into the nucleus to exert part of their biological functions. The transport mechanisms that shuttle molecules through the nuclear membrane and their regulation are a research subject in relation to oxygen dependent gene regulation.

(3) Organ perfusion is regulated by diameter changes of the smallest arteries (arterioles). The arteriolar diameters are controlled by endothelial cells, which form the innermost cell layer in vessels. The endothelium modulates the activity of the adjacent smooth muscle cell by releasing different dilator and constrictor mediators and thereby exerts its control function on vascular tone and thus blood flow. Endothelial function is studied by means of intravital microscopy in the skeletal muscle of mice, using the isolated perfused heart or isolated vessels but also by telemetric measurement of arterial pressure in conscious animals. The arterioles that provide and control blood flow to the tissues can be directly observed using intravital microscopy. Thus, vascular diameter, blood flow velocity, and the membrane potential of vascular cells (endothelial and smooth muscle cells) can be directly assessed. A topic of special interest is the coordination of vascular cell behaviour along the length of the vessel as vascular cells do not act independently of each other but form a coordinated cellular network. Many vasomotor stimuli do not only elicit a diameter change at the site of localized application but also induce diameter changes at remote upstream sites without stimulating these areas directly. Such remote vascular responses (conducted response) require intercellular connections allowing signals to be transmitted from cell to cell. The molecular bricks of these channels are the connexin proteins which cluster to form so-called gap junctions. Overall, the studies are aimed to examine the role of endothelial mediators and gap junction proteins (connexins) in the control of blood flow to the tissues.

(4) In collaboration with the Department for Integrative and Experimental Genomics, genes that have been demonstrated to be associated with myocardial infarction and coronary disease are examined to identify their functional roles in physiologic and pathophysiologic models. Hitherto, blood pressure measurement, development of atherosclerosis, and thrombus formation are studied in vivo in gene-deficient mice. The studies are aimed to identify how certain genes lead to coronary diseases and provide new ideas for treatment strategies.

(5) Isolated perfused kidneys of mice and rats are used as a model to study renal effects of hormones and drugs.