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Forschung

MICROENVIRONMENTAL SIGNALS IN HEALTH AND DISEASE
IN THE CENTRAL NERVOUS SYSTEM

Our lab’s long-standing interest focuses on how microenvironmental cues, particularly hypoxia, participate in the regulation of adaptive responses to pathological stimuli, particularly in tumor / tumor stem cell growth, cerebral ischemia and neural stem cell growth. We have dissected the differential functions of the key transcriptional regulators that mediate the hypoxia response (hypoxia inducible factor (HIF)-1alpha and HIF-2alpha) and their downstream targets in various pathological settings in the CNS

Experimentally we use a panel of glioblastoma tumor (stem) cell lines, biospies, 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. To elucidate the role of the hypoxia response we employ a wide spectrum of methods: cloning, cell culture, biochemistry, quantitative RT-PCR, FACS, ELISA, cell-based assays (proliferation, apoptosis, migration, 3D invasion etc.), virally-based gene delivery and RNAi silencing, immunohistochemistry, in situ hybridization, light, epifluorescence and confocal microscopy, image analysis, animal models and in vivo transplantation.

We offer an open, supportive, internationally competitive academic environment with excellent training opportunities within the PhD graduate program of the International Giessen Graduate school for Life Sciences (GGL: http://www.uni-giessen.de/cms/fbz/zentren/ggl). We have won a number of external research grants and are involved in several national and international collaborative projects.

The following links provide an overview of our research projects, further details about our main areas of interest, including tumor hypoxia, tumor stem cells, and cerebral ischemia, as well as a list of selected publications.

For current job openings at the Institute, please click here.

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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....

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Tumor Hypoxia

Regions of low oxygen tension are common findings in malignant tumors being associated with increased frequency of tumor invasion and metastasis, thus critically determining the clinical behaviour of tumors. Indeed, the ability to initiate homeostatic responses and adapt to hypoxia, e.g. by induction of angiogenesis, represents a central driving force in solid tumor growth, crucially governed by the key transcriptional regulators HIF-1α and HIF-2α. Tumor growth and vascularization are inherently dependent on an intricate molecular and cellular crosstalk within the tumor microenvironment. Interestingly, apart from endothelial and perivascular cells tumors attract a number of cell types including inflammatory/hematopoietic cells and circulating endothelial precursor (CEP) cells. These synergistically act to augment vascularization of the tumor. Current studies indicate that tumor hypoxia and HIF not only indirectly influences these cell types by tumor cell specific upregulation of various secreted, paracrine acting factors but may in addition have direct cell-intrinsic effects....

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Tumor Stem Cells

One of the crucial questions in tumor biology is the identity of the cell and cellular programme that drive tumor growth. Two models best describe the growth characteristics of tumors: the stochasctic and the hierarchy model. The stochastic model postulates that each cell within the tumor has the same capacity to proliferate and thus sustain tumor growth. Tumor heterogeneity is explained by the existence of multiple genetic tumor subclones, due to cumulative acquisition of genetic alterations. Conversely, the hierarchy model assumes that only a small subpopultation of tumor cells has the capacity to initiate and drive tumor growth, the so called tumor stem cells. This specialized cell type possesses the key stem cell characteristics, namely self renewal and multipotency. It gives rise to a more differentiated progeny that has lost the ability to initiate tumor growth. Thus, the hierarchy model adds stem cell differentiation as an additional factor to explain tumor heterogeneity. Consequently, the hierarchy model crucially challenges our current concept of tumor research and treatment, that has concentrated on the bulk of tumor cells, potentially missing out on the decisive mechanisms that regulate tumor stem cells. In analogy to physiological stem cell homeostasis, self renewal and differentiation mechanisms may critically influence tumor stem cell biology....

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Cerebral Ischemia

In the adult organism, cerebral ischemia is commonly precipitated by embolic vessel obstruction resulting in reduction or complete loss of perfusion in downstream fields. Neuronal loss, tissue edema and tissue necrosis ensue. Following pemanent middle cerebral artery occlusion in rats we observed a marked induction of HIF-2α in neurons, closely followed, temporally and spatially, by upregulation of HIF-2α target genes such as VEGF, Epo (Erythropoietin) and VEGFR-2. Our results suggest that HIF-2α could be an important regulator of ischemia-induced responses particularly in neurons and might promote cell survival after ischemia by increasing glucose transport, upregulation of potentially neuroprotective factors (VEGF, Epo) and induction of angiogenesis....