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Platelet dynamics in natural and pharmacologically induced hibernation

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Title:  Platelet dynamics in natural and pharmacologically induced hibernation.
Investigator:  EL de Vrij
Promotor:  RH Henning
Co-promoter(es):   HR Bouma
Summary:  Blood platelets serve primarily to initiate hemostasis following blood vessel injury. In addition to a myriad of other processes, platelets are also involved in the pathogenesis of thrombo-embolic processes and inflammatory responses.

Cardiopulmonary bypass (CPB) is a commonly used technique that allows cardiac surgery under cardiac arrest. We hypothesize that inappropriate activation of platelets plays a significant role in the pathogenesis of renal injury following CPB. Platelet activation results in a widespread activation of the hemostatic system, associated with postoperative coagulation defects and organ dysfunction. Likely, platelets are involved in the pathogenesis of organ injury through formation of emboli and amplification of the inflammatory response.

Prevention of platelet activation might reduce post-operative morbidity and mortality following CPB. Mammalian hibernation, divided in periods of torpor and arousal, might yield new tools to prevent organ dysfunction and postoperative bleeding time in CPB patients. Despite the potential procoagulant state of hibernation due to hypothermia, low blood flow, increased blood viscosity, immobility, hypoxia and repetitive cooling and rewarming, no signs of platelet activation or organ injury can be found. The experiments proposed in this research investigate the changes in coagulation during hibernation, specifically focusing on platelet count and function, and the applicability in a CPB model.


In this research we intend to identify the underlying mechanisms in hibernators that prevent thrombo-embolic processes, and to exploit these mechanisms in CPB. We propose to characterize platelet amounts, function and localization during hibernation (torpor and arousal) and to assess whether platelet function is affected by temperature-independent factors including H2S. Finally, we aim to assess whether pharmacologically induced thrombocytopenia protects from organ damage during cardiopulmonary bypass (CPB).

Financing:  Junior Scientific Masterclass, MD/PhD bursary, de Cock Foundation
Start:  1-11-2013
End:  1-11-2016 
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.