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Mechanisms and modulation of the immune response in sterile sepsis

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Title:   Mechanisms and modulation of the immune response in sterile sepsis
Investigator:  VA Reitsema
Promotor:  RH Henning, FGM Kroese
Co-promoter(es):   HR Bouma
Summary:

This research intends to discover mechanisms in hibernators that modulate immune responses in sterile sepsis. Sepsis is a systemic inflammatory response that can lead to severe organ damage. In only fifty percent of septic patients, sepsis is linked to an infectious organism. One of the causes for such 'sterile infection' is ischemia-reperfusion injury. Although sepsis is associated with high mortality rates, there is no FDA-approved drug for modulation of the immune response in sepsis. Hibernation might provide the answers for adequate immune modulation and prevention of organ damage. Hibernation consists of periods of lowered metabolism and body temperature (torpor), alternating with euthermic periods (arousals). Interestingly, several cycles of torpor and arousal nor ischemia-reperfusion lead to organ damage in hibernators. Reversible immune suppression is believed to constitute one of the organ protective mechanisms in hibernation. During torpor, levels of circulating leukocytes (mainly neutrophils and lymphocytes) drop by 90% and lymphocytes show reduced functionality. Sphingosine-1-phosphate (S1P) and the S1P receptor 1 (S1P1) have important roles in the regulation of lymphocyte function and are implicated in the lymphopenia found in hibernators during torpor. The experiments proposed in this research investigate the role of the innate (tissue resident macrophages) and adaptive (lymphocytes) immune system in hibernation, specifically focusing on the role of S1P and S1P1, and their applicability in a model of sterile sepsis. Research question: What are the underlying mechanisms in hibernators that modulate the innate as well as the adaptive immune responses, and how can we exploit these mechanisms in sterile sepsis? We propose 5 aims to investigate the research question:

1. Establish the role of sphingosine-1-phosphate, sphingosine kinase-1 and ATP-binding cassette C1 transporter in the regulation of lymphocyte proliferation.

2. Determine the role of S1P1 in lymphocyte recirculation in hibernation.

3. Assess the functionality of TLRs in complement and T-cell independent B-cell function during torpor and arousal.

4. Assess whether disruption of the S1P feed-forward system on any level precludes a T-cell response in sterile sepsis and thereby prevent kidney and lung damage.

5. Identify the role of tissue resident macrophages in the resistance of hibernators to ischemia-reperfusion damage.

Financing:   Junior Scientific Masterclass, MD/PhD bursary
Start: 1-05-2014
End:  1-05-2017 

 

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.