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Organ damage and the role of CBS in hibernation

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Title:  Organ damage and the role of CBS in hibernation
Investigator:  M Tolouee Nadolaghi
Promotor:  RH Henning
Summary:  Adequate coping with oxidative and nitrosative stress is an important factor in determining lifespan and health span. Boosting a subject's oxidant defense promotes longevity and mitigates the progression of disease in highly prevalent conditions including diabetes and cardiovascular, neurologic and renal diseases.   Unfortunately, the search for novel therapeutics proved to be more difficult than anticipated, as potent anti-oxidants in chemical systems did not show beneficial effects in biological systems. Currently, it is accepted that potentially successful compounds do not primarily act as radical scavengers in vivo, but rather inhibit mechanisms that produce oxidants, such as NO and ROS (reactive oxygen species), or promote the activity of endogenous anti-oxidant pathways. In theory, such compounds may prove even superior efficacy in limiting production of ROS, should they additionally chelate transition metal ions or alter their valent state.

To identify novel anti-oxidant drugs and drugable targets, we recently explored a unique and natural model of coping with repetitive oxidative stress and limiting organ damage: hibernators. During hibernation animals alternate between periods of 95% reduction of metabolism and low body temperatures (1-4 DC) and periods of excessive metabolism and full restoration of body temperature and physiology. Yet, despite the repetitive and high oxidative burden during rewarming, hibernators do not show signs of organ injury. We showed biogenic amines (e.g. dopamine, serotonin) to counteract oxidative stress through the endogenous production of hydrogen sulfide (H2S) by the enzyme cystathionine beta synthase (CBS). Preliminary experiments showed that serotonin and dopamine induce H2S through both allosteric activation and up-regulation of CBS. The in situ formed H2S most likely protects against ROS formed during the warming-up phase, particularly in mitochondria. As the CBS enzyme is also available in humans, targeting might be of interest for treatment of diseases of aging and oxidative stress.

In this study we seek to determine the regulation of CBS in various organs from hibernating animals and to explore the effectiveness of hibernation-derived compounds on mitigating hypothermic cell damage.

Financing:   Special PhD bursary scheme GUIDE
Start: 1-12-2012
End:   1-12-2016

 

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.