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Institute of Physiology and Pathophysiology

Research Areas

Hypoxia in the Brain

Our research group investigates the effects of hypoxia in the brain. Tissue hypoxia in the brain is a central problem in a number of disorders such as ischemia, tumors, brain injury, high altitude sickness and epilepsy. The insufficient availability of oxygen to the cells can be caused by reduced supply or increased consumption. Therefore our interest is focused on the neurovascular interplay which also includes glial cells. We study two hypoxia-related processes in particular: 1) the activation of endogenous factors which protect neurons against cell death or which induce their regeneration (neuroprotection and neurogenesis), and 2) the opening of the blood-brain barrier leading to cerebral oedema formation. We utilise various in vivo experimental models (hypoxia chamber, ischemia models), including transgenic animals, and combine these with modern molecular biology techniques. By analysing and characterising this endogenous protective response we hope to find clues for new therapies for human diseases.

1) Neuroprotection and Neurogenesis


Tissue hypoxia is detected via various oxygen sensors (polylhydoxylases, PHD), which activate specific transcription factors (hypoxia-inducible factors, HIF), which, in turn, lead to the induction of neurogenic and neuroprotective factors such as vascular endothelial growth factor (VEGF) or erythropoietin (Epo). It is the aim of our research to understand in detail the underlying mechanisms and to manipulate them in a positive way.




Brain-specific overexpression of VEGF reduces infarct (pale area) size. Infarct size quantification on cresyl violet-stained brain tissue sections revealed a significant 40% reduction in VEGF transgenic mice (VEGF-tg) as compared with non transgenic littermate controls (ntg).

 

from Wang et al.; Brain (2005); 128: 52-63

2) Blood-Brain Barrier


Besides its positive properties (neuroprotection, neurogenesis, angiogenesis) VEGF has one negative effect on the blood-brain barrier (BBB), which complicates its immediate therapeutic use:  VEGF leads to the opening of the BBB and, as a consequence, to the formation of a cerebral oedema. We investigate the molecular mechanisms of this opening by characterising the processes at the endothelial cell-cell contacts (tight junctions) and at the extracellular matrix. It is our goal to reduce oedema formation by intervention without affecting the neuroprotective properties.

 


Hypoxia causes rearrangement and gap formation of the tight junction protein occludin. Mice were exposed for 48 h to 20% (control) or 8% oxygen (hypoxia). Coronal brain sections were
stained immunohistochemically for occludin (green) and CD31 (red), and nuclei were stained with DAPI (blue). Three-dimensional reconstruction after confocal microscopy demonstrates occludin rearrangement and gap formation (arrowheads) after hypoxia, as compared to the continuous, sharp linear staining (arrows) in controls.

 

from Bauer et al.; J Cereb Blood Flow Metab (2010); 30: 837-848.





Recent Publications

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Assembly of vascular smooth muscle cells in 3D aggregates provokes cellular quiescence. Exp Cell Res. 2020 Mar 1;388(1):111782. doi: 10.1016/j.yexcr.2019.111782. Epub 2019 Dec 16.

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Clusters of cooperative ion channels enable a membrane-potential-based mechanism for short-term memory. Elife. 2020 Feb 7;9. pii: e49974. doi: 10.7554/eLife.49974.

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AAV-mediated TIMP-1 overexpression in aortic tissue reduces the severity of allograft vasculopathy in mice. J Heart Lung Transplant. 2020 Jan 30. pii: S1053-2498(20)31356-5. doi: 10.1016/j.healun.2020.01.1338. [Epub ahead of print]

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Mepivacaine reduces calcium transients in isolated murine ventricular cardiomyocytes. BMC Anesthesiol. 2020 Jan 8;20(1):10. doi: 10.1186/s12871-019-0926-0.

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Factors determining microbial colonization of liquid nitrogen storage tanks used for archiving biological samples. Appl Microbiol Biotechnol. 2020 Jan;104(1):131-144. doi: 10.1007/s00253-019-10242-1. Epub 2019 Nov 28.

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Shaping the heart: Structural and functional maturation of iPSC-cardiomyocytes in 3D-micro-scaffolds. Biomaterials. 2020 Jan;227:119551. doi: 10.1016/j.biomaterials.2019.119551. Epub 2019 Oct 19.

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Simulation Strategies for Calcium Microdomains and Calcium Noise. Adv Exp Med Biol. 2020;1131:771-797. doi: 10.1007/978-3-030-12457-1_31.

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Tyrphostin AG490 reduces inflammation and fibrosis in neonatal obstructive nephropathy. PLoS One. 2019 Dec 17;14(12):e0226675. doi: 10.1371/journal.pone.0226675. eCollection 2019.

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Mild metabolic stress is sufficient to disturb the formation of pyramidal cell ensembles during gamma oscillations. J Cereb Blood Flow Metab. 2019 Dec 16:271678X19892657. doi: 10.1177/0271678X19892657. [Epub ahead of print

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Risk and protective factors for post-thrombotic syndrome after deep venous thrombosis. J Vasc Surg Venous Lymphat Disord. 2019 Dec 13. pii: S2213-333X(19)30537-2. doi: 10.1016/j.jvsv.2019.10.012. [Epub ahead of print]

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AAV-Mediated Expression of AP-1-Neutralizing RNA Decoy Oligonucleotides Attenuates Transplant Vasculopathy in Mouse Aortic Allografts. Mol Ther Methods Clin Dev. 2019 Dec 13;15:246-256. doi: 10.1016/j.omtm.2019.09.009. eCollection 2019 Dec 13. Epub 2019 Oct 2.

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Amyloid, APP, and Electrical Activity of the Brain. Neuroscientist. 2019 Nov 29:1073858419882619. doi: 10.1177/1073858419882619. [Epub ahead of print]

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The mitochondrial calcium uniporter is crucial for the generation of fast cortical network rhythms. J Cereb Blood Flow Metab. 2019 Nov 13:271678X19887777. doi: 10.1177/0271678X19887777. [Epub ahead of print]

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Somatic mutations and promotor methylation of the ryanodine receptor 2 is a common event in the pathogenesis of head and neck cancer. Int J Cancer. 2019 Dec 15;145(12):3299-3310. doi: 10.1002/ijc.32481. Epub 2019 Jun 19.

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Loss of the serine protease HTRA1 impairs smooth muscle cells maturation. Sci Rep. 2019 Dec 3;9(1):18224. doi: 10.1038/s41598-019-54807-6.

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Persistent increase in ventral hippocampal long-term potentiation by juvenile stress: A role for astrocytic glutamine synthetase. Glia. 2019 Dec;67(12):2279-2293. doi: 10.1002/glia.23683. Epub 2019 Jul 17.

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Functional association of a CD40 gene single nucleotide polymorphism with the pathogenesis of coronary heart disease. Cardiovasc Res. 2019 Aug 2. pii: cvz206. doi: 10.1093/cvr/cvz206. [Epub ahead of print]


Institute of
Physiology and Pathophysiology

Heidelberg University

Im Neuenheimer Feld 326

69120 Heidelberg

Germany

Phone:+49 6221 54-4056
Fax:+49 6221 54-6364
E-mail:susanne.bechtel@
physiologie.uni-heidelberg.de