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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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Induced Pluripotent Stem Cell-derived cardiomyocytes (iPSC-CMs); generation and enrichment protocols, immature and mature structure and function. In: Recent Advances in iPSC-Derived Cell Types, Volume 4, 1st Edition (Birbrair A, ed.) Academic Press 2021, pp. 191-226. Paperback ISBN 9780128222300; eBook ISBN 9780128224540

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Epigenetic regulation of cardiac electrophysiology in atrial fibrillation: HDAC2 determines action potential duration and suppresses NRSF in cardiomyocytes. Basic Res Cardiol. 2021 Feb 25;116(1):13. doi: 10.1007/s00395-021-00855-x. PMID: 33630168

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Endothelial cells control vascular smooth muscle cell cholesterol levels by regulating 24-dehydrocholesterol reductase expression. Exp Cell Res. 2021 Feb 15;399(2):112446. doi: 10.1016/j.yexcr.2020.112446. Epub 2021 Jan 7.

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Integrated information theory does not make plant consciousness more convincing. Biochem Biophys Res Commun. 2021 Jan 21:S0006-291X(21)00057-7. doi: 10.1016/j.bbrc.2021.01.022. Online ahead of print.

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AAV-mediated AP-1 decoy oligonucleotide expression inhibits aortic elastolysis in a mouse model of marfan syndrome. Cardiovasc Res. 2021 Jan 20:cvab012. doi: 10.1093/cvr/cvab012. Online ahead of print.

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Voltage-independent GluN2A-type NMDA receptor Ca2+ signaling promotes audiogenic seizures, attentional and cognitive deficits in mice. Commun Biol. 2021 Jan 8;4(1):59. doi: 10.1038/s42003-020-01538-4.

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A thalamic bridge from sensory perception to cognition. Neurosci Biobehav Rev. 2021 Jan;120:222-235. doi: 10.1016/j.neubiorev.2020.11.013. Epub 2020 Nov 24.

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Assessable learning outcomes for the EU Education and Training Framework core and Function A specific modules: Report of an ETPLAS WORKING Group. Lab Anim. 2020 Dec 7:23677220968589. doi: 10.1177/0023677220968589. Online ahead of print.

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Pflügers Archiv - European journal of physiology becomes the official journal of the German Physiological Society. 2020 Dec;472(12):1657. doi: 10.1007/s00424-020-02493-z. Editorial. No abstract available.

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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. 2020 Dec;40(12):2401-2415. doi: 10.1177/0271678X19892657. Epub 2019 Dec 16.

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Gene transfer to the vascular system: Novel translational perspectives for vascular diseases. Biochem Pharmacol. 2020 Dec;182:114265. doi: 10.1016/j.bcp.2020.114265. Epub 2020 Oct 6. Review.

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Alterations of distributed neuronal network oscillations during acute pain in freely-moving mice. IBRO Rep. 2020 Dec;9:195-206. doi: 10.1016/j.ibror.2020.08.001. eCollection 2020 Dec. Epub 2020 Aug 11.

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Debunking a myth: plant consciousness. Protoplasma. 2020 Nov 16. doi: 10.1007/s00709-020-01579-w. Review. Online ahead of print.

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Anesthetics and plants: no pain, no brain, and therefore no consciousness. Protoplasma. 2020 Sep 2. doi: 10.1007/s00709-020-01550-9. Online ahead of print.

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Microglia and lipids: how metabolism controls brain innate immunity. Semin Cell Dev Biol. 2020 Aug 14;S1084-9521(19)30197-1. doi: 10.1016/j.semcdb.2020.08.001. Online 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