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Overview

The structural and functional integrity of the brain profoundly depend on a regular supply of oxygen and glucose. Any disturbance of this supply becomes life threatening and may result in severe loss of brain function. In particular, reduction in oxygen availability (hypoxia) caused by systemic or local blood circulation irregularities cannot be tolerated for long periods due to an insufficient energy supply of the brain by anaerobic glycolysis. Complex cellular oxygen sensing systems have evolved to tightly regulate oxygen homeostasis in the brain, inducing adaptive mechanisms in response to variations in oxygen tension to avoid or minimize brain damage. A mounting body of evidence suggests that identical signaling mechanisms are recruited and activated in a range of CNS pathologies including neoplasia, cerebral ischemia, head trauma, vascular malformation and neurodegenerative diseases, determining critical pathophysiological and clinical parameters of these disorders.


  Fig. 1

A significant advance in our understanding of the hypoxia response stems from the discovery of the hypoxia inducible transcription factors HIF-1alpha and HIF-2alpha, which act as key regulators of hypoxia-induced gene expression. HIF activity is tightly controlled by an oxygen sensing cascade comprising a subfamily of 2-oxoglutarate dependent dioxygenases termed HIF prolylhydroxylases (PHDs) which employ non-heme iron in their catalytic moiety to induce HIF ubiquitylation and degradation (Fig. 1).

A second oxygen dependent switch in the control of HIF activity is constituted by factor inhibiting HIF (FIH), regulating the transactivation capacity of HIF-α subunits. Depending on the duration and the severity of oxygen deprivation cellular oxygen sensor responses activate a variety of short- and long-term energy-conserving cellular mechanisms. HIF mediated gene expression induces a variety of mechanisms such as angiogenesis (i.e. VEGF [vascular endothelial growth factor]), a shift in energy metabolism to anaerobic glycolysis (i.e. lactate dehydrogenase), cell survival (i.e. insulin like growth factors 1 and 2) or neural stem cell growth (i.e. erythropoietin, VEGF).

Our lab focuses on elucidating how and to what extent HIF, PHD and FIH participate in the regulation of adaptive responses to pathological stimuli, particularly in tumor / tumor stem cell growth, cerebral ischemia, neural stem cell growth and vascular malformations. We use a panel of glioblastoma tumor cell lines, primary human endothelial cells and murine adult neural stem cells, as well as different transgenic mouse lines, as experimental in vitro and in vivo model systems.

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