Project Details
Description
1) EXPLORING CANCER'S RESISTANCE AGAINST CELL DEATH TO FIGHT HEART DISEASE
The role of the glycolytic enzyme hexokinase and its binding to mitochondria in cell death in healthy, diabetic, remodelled and I/R hearts is investigated.
The underlying hypothesis is that our main energy factory, the mitochondrion, a proto-bacterium that invaded the eukaryotic cell about 2 miljard years ago, is kept in check by a protein hexokinase, that belongs to the pre-exisitng energy production pathway, the glycolysis. It is now clear that many forms of cell death are initiated by the mitochondrion, and that hexokinase may be viewed as a gatekeeper of this important energy / dead factory. Part of the resistance of cancer cell against cell death is probably due to its high (> 10 x) expression of hexokinase bound to mitochondria. We were the first to show that this protective mechanism may also be explored for the heart. In this project we explore whether ther heart can also use this protective mechanism against cell death, and whether pathologies with increased incidence of cardiac diseases can be traced down to diminished amounts of hexokinase (diabetes, heart failure, unprotected hearts)
Collaboration: dr Rick Southworth, King's College London; dr Fadi Akar & dr C. Xie, Mount Sinai Medical Center, New York; dr Hossein Ardehali & dr R Wu, Northwestern University, Chicago; dr Otto Eerbeek, department Physiology, AMC
2) INFLAMMATION AND CARDIAC ISCHEMIA-REPERFUSION INJURY: MORE SIMILAR THAN YOU THINK
Inflammation and ischemie-reperfusie injury often have similar celluar trigger mechanisms. In this project we examine how our innate immune system affects cardiac ischemia-reperfusion and protection induced by ischemic preconditioning, by focussing on the NLRP inflammasome.
Collaboration; dr Jaklien Leemans, department Pathology, AMC
3) OXYGEN IS A MAIN REGULATOR OF LIFE AND OUR HEART
At this moment in time the amount of oxygen arounds us is 21%. However, there were times that this amount was > 30% (500-600 mlj years ago); in that time insects were giants, suggesting that the oxygen around us sets limits to the size of living organisms. We may all be oxygen-limited. The heart is the organ in our body with the highest oxygen need, and may therefore be most oxygen-limited. Using innovative technology allowing in vivo determination of mitochondrial oxygen tension level, developed by dr E. Mik, we hypothesize in this project that the amount of oxygen available for our energy factories, the mitochondria (the place were our oxygen is actually needed!), determines cardiac function and survival in healthy and failing hearts
Collaboration: dr. E Mik, Erasmus University Rotterdam; dr WJ van der Laarse, VU Amsterdam
4) Protecting the GLYCOCALYX and HEART cell during surgery-mimicking conditions in diseased states
We were the first to show, in collaboration with dr. H Vink, that the glycocalyx was affected by diabetes and hyperglycemia, probably through oxidative stress (Zuurbier CJ et al, J Appl Physiol 2005), and may well explain the leaky blood vessels known to occur with high blood glucose. In this project we examine whether eNOS coupling condtions may protect against I/R injury of the myocyte and glycocalyx, mitigating edema formation and reperfusion injury that so often occur during surgical procedures.
Collaboration: dr. J.W. van Teeffelen, Maastricht University; dr. Andre Heinen, University Dusseldorf, Germany
5) The interaction between ANESTHESIA, METABOLISM and INFLAMMATION; Optimizing Anesthesia for Animal Research
Usually, the anesthesiologist works in separate fields as the endocrinologist or the internist. However, as always, it all interacts. In this reseach line we examine how different anesthetic regimens affect metabolic (glucose, insulin, FFA) and inflammatory parameters. Our final goal is to optimize anesthetic regimens to allow high-quality animal research, with important spin-offs to the clinical arena.
Collaboration: dr W. Florijn, DEC, AMC, Anneke van der Graaf, dr. S Houten, Lab. Genetic Metabolic Diseases
The role of the glycolytic enzyme hexokinase and its binding to mitochondria in cell death in healthy, diabetic, remodelled and I/R hearts is investigated.
The underlying hypothesis is that our main energy factory, the mitochondrion, a proto-bacterium that invaded the eukaryotic cell about 2 miljard years ago, is kept in check by a protein hexokinase, that belongs to the pre-exisitng energy production pathway, the glycolysis. It is now clear that many forms of cell death are initiated by the mitochondrion, and that hexokinase may be viewed as a gatekeeper of this important energy / dead factory. Part of the resistance of cancer cell against cell death is probably due to its high (> 10 x) expression of hexokinase bound to mitochondria. We were the first to show that this protective mechanism may also be explored for the heart. In this project we explore whether ther heart can also use this protective mechanism against cell death, and whether pathologies with increased incidence of cardiac diseases can be traced down to diminished amounts of hexokinase (diabetes, heart failure, unprotected hearts)
Collaboration: dr Rick Southworth, King's College London; dr Fadi Akar & dr C. Xie, Mount Sinai Medical Center, New York; dr Hossein Ardehali & dr R Wu, Northwestern University, Chicago; dr Otto Eerbeek, department Physiology, AMC
2) INFLAMMATION AND CARDIAC ISCHEMIA-REPERFUSION INJURY: MORE SIMILAR THAN YOU THINK
Inflammation and ischemie-reperfusie injury often have similar celluar trigger mechanisms. In this project we examine how our innate immune system affects cardiac ischemia-reperfusion and protection induced by ischemic preconditioning, by focussing on the NLRP inflammasome.
Collaboration; dr Jaklien Leemans, department Pathology, AMC
3) OXYGEN IS A MAIN REGULATOR OF LIFE AND OUR HEART
At this moment in time the amount of oxygen arounds us is 21%. However, there were times that this amount was > 30% (500-600 mlj years ago); in that time insects were giants, suggesting that the oxygen around us sets limits to the size of living organisms. We may all be oxygen-limited. The heart is the organ in our body with the highest oxygen need, and may therefore be most oxygen-limited. Using innovative technology allowing in vivo determination of mitochondrial oxygen tension level, developed by dr E. Mik, we hypothesize in this project that the amount of oxygen available for our energy factories, the mitochondria (the place were our oxygen is actually needed!), determines cardiac function and survival in healthy and failing hearts
Collaboration: dr. E Mik, Erasmus University Rotterdam; dr WJ van der Laarse, VU Amsterdam
4) Protecting the GLYCOCALYX and HEART cell during surgery-mimicking conditions in diseased states
We were the first to show, in collaboration with dr. H Vink, that the glycocalyx was affected by diabetes and hyperglycemia, probably through oxidative stress (Zuurbier CJ et al, J Appl Physiol 2005), and may well explain the leaky blood vessels known to occur with high blood glucose. In this project we examine whether eNOS coupling condtions may protect against I/R injury of the myocyte and glycocalyx, mitigating edema formation and reperfusion injury that so often occur during surgical procedures.
Collaboration: dr. J.W. van Teeffelen, Maastricht University; dr. Andre Heinen, University Dusseldorf, Germany
5) The interaction between ANESTHESIA, METABOLISM and INFLAMMATION; Optimizing Anesthesia for Animal Research
Usually, the anesthesiologist works in separate fields as the endocrinologist or the internist. However, as always, it all interacts. In this reseach line we examine how different anesthetic regimens affect metabolic (glucose, insulin, FFA) and inflammatory parameters. Our final goal is to optimize anesthetic regimens to allow high-quality animal research, with important spin-offs to the clinical arena.
Collaboration: dr W. Florijn, DEC, AMC, Anneke van der Graaf, dr. S Houten, Lab. Genetic Metabolic Diseases
Status | Active |
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Effective start/end date | 1/08/2012 → … |