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The CBS/H2S pathway in the brain

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Title:  The CBS/H2S pathway in the brain
Investigator:  JJ Bruintjes
Promotor:  RH Henning, EA vd Zee
Summary:  Hibernating animals do not develop organ damage during their repetitive cycles of cooling-rewarming (torpor-arousal) and hence may serve as a paradigm for organ protection. This also applies to the brain, as hibernators show signs of brain damage, such as tau hyperfosforylation and loss of synaptic integrity, which is rapidly normalized after returning to euthermia. We previously coined the cystathionine beta synthase/hydrogen sulphide (CBS/H2S) pathway as an important protective mechanism. Moreover, pharmacological stimulation of the CBS/H2S pathway conveys protection from cooling/rewarming in cells. CBS expression is particularly high in brain, however its physiologic relevance is unknown. We hypothesize that the CBS/H2S pathway plays an important role in brain, due to its protective abilities. As such it may be involved in the pathogenesis of neurodegenerative diseases such as Alzheimer's Disease (AD). To this end we will analyze CBS expression in multiple animal species and in different conditions in the absence and presence of a blockade of CBS. Also, possible protective mechanisms of the CBS/H2S pathway will be explored in cultured neurons challenged with different types of damage. In these cells the CBS/H2S pathway will be modulated by genetic approaches and pharmacological compounds. Finally we will investigate the protective mechanisms of the CBS/H2S pathway in neurodegeneration by examining brains of transgenic Alzheimer's Disease (AD) mice and, if possible, human AD brains. 
Financing:  Junior Scientific Masterclass, MD/PhD bursary
Start:  1-04-2013
End:  1-04-2017 

 

Projects
Organ damage and the role of CBS in hibernation.
Mechanisms and modulation of the immune response in sterile sepsis.
The CBS/H2S pathway in the brain.
Platelet dynamics in natural and pharmacologically induced hibernation.
Liver fibrosis and hibernation.
Towards prevention of neuroinflammation in major surgery.
Limiting the impact of stroke.
Identification of kinomic key proteins involved in tachycardia and stretch induced cardiomyocyte remodeling.
Role of epigenetic regulation by histone acetylation in the induction of Atrial Fibrillation.
Reversal of cardiomyocyte remodeling in Atrial Fibrillation; the role of protein degradation and translation modulators.
REVersal of cardiomyocyte structural remodeling and Improvement of functional recoVEry in Atrial Fibrillation: REVIVE.
HSF1 Activators Lower cardiomyocyte damage: towards a novel Therapeutic approach to REVERSE Atrial Fibrillation. HALT&REVERSE
Mutations in HSPB5, HSPB7 and BAG3 lead to juvenile DCM.
New therapeutic targets in diabetic kidney disease. A role of GDF-15?
Role of cyclooxygenase signalling on vascular dysfunction in the metabolic syndrome.
Vascular (Dys-)Function as a Determinant of Susceptibility to Diabetic Nephropathy: a Focus on Myogenic Constriction.