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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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Metabolic modulation of neuronal gamma-band oscillations. Pflugers Arch2018 Sep;470(9):1377-1389. doi: 10.1007/s00424-018-2156-6. Epub 2018 May 28.

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Electrical coupling between hippocampal neurons: contrasting roles of principal cell gap junctions and interneuron gap junctions. Cell Tissue Res. 2018 Aug 15. doi: 10.1007/s00441-018-2881-3. [Epub ahead of print] Review.

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Selective vulnerability of αOFF retinal ganglion cells during onset of autoimmune optic neuritis. Neuroscience. 2018 Jul 31. pii: S0306-4522(18)30515-3. doi: 10.1016/j.neuroscience.2018.07.040. [Epub ahead of print]

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Strategy for marker-based differentiation of pro- and anti-inflammatory macrophages using matrix-assisted laser desorption/ionization mass spectrometry imaging. Analyst. 2018 Jul 20. doi: 10.1039/c8an00659h. [Epub ahead of print]

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Improving electrical properties of iPSC-cardiomyocytes by enhancing Cx43 expression. J Mol Cell Cardiol. 2018 Jul;120:31-41. doi: 10.1016/j.yjmcc.2018.05.010. Epub 2018 May 16.

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Role of CD40 and ADAMTS13 in von Willebrand factor-mediated endothelial cell-platelet-monocyte interaction. Proc Natl Acad Sci U S A. 2018 Jun 12;115(24):E5556-E5565. doi: 10.1073/pnas.1801366115. Epub 2018 May 23.

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The VAMP-associated protein VAPB is required for cardiac and neuronal pacemaker channel function. FASEB J. 2018 Jun 7:fj201800246R. doi: 10.1096/fj.201800246R. [Epub ahead of print]

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Persistent sodium current modulates axonal excitability in CA1 pyramidal neurons. J Neurochem. 2018 Jun 4. doi: 10.1111/jnc.14479. [Epub ahead of print]

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The lncRNA CASC9 and RNA binding protein HNRNPL form a complex and co-regulate genes linked to AKT signaling. Hepatology. 2018 May 23. doi: 10.1002/hep.30102. [Epub ahead of print]

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Early Blood-Brain Barrier Disruption in Ischemic Stroke Initiates Multifocally Around Capillaries/Venules. Stroke. 2018 Jun;49(6):1479-1487. doi: 10.1161/STROKEAHA.118.020927. Epub 2018 May 14.

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Impact of carbonylation on glutathione peroxidase-1 activity in human hyperglycemic endothelial cells. Redox Biol. 2018 Jun;16:113-122. doi: 10.1016/j.redox.2018.02.018. Epub 2018 Mar 1.

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Endothelial progenitor cells accelerate endothelial regeneration in an in vitro model of Shigatoxin-2a-induced injury via soluble growth factors. Am J Physiol Renal Physiol. 2018 Mar 7. doi: 10.1152/ajprenal.00633.2017. [Epub ahead of print]


Institute of
Physiology and Pathophysiology

Heidelberg University

Im Neuenheimer Feld 326

69120 Heidelberg

Germany

Phone:+49 6221 54-4035
Fax:+49 6221 54-4038
E-mail:sekretariat.hecker@
physiologie.uni-heidelberg.de