Department of Intensive Care Medicine
Oxygenation in critically ill patients
Hyperoxemia may increase organ dysfunction in critically ill patients, but optimal oxygenation targets are unknown. In a large multicenter randomized clinical trial in 4 intensive care units in the Netherlands we investigated whether a low-normal PaO2 target (8 to 12 kPa) compared with a high-normal target (14 – 18 kPa) reduced organ dysfunction in critically ill patients with systemic inflammatory response syndrome (SIRS). A low-normal PaO2 target compared with a high-normal PaO2 target did not result in a statistically significant reduction in organ dysfunction. Find our previous publication about this topic here
We want to analyze in more detail the effect of 2 different oxygenation targets on cardiovascular function and lung injuries. This is a project for 2 students.
We aim to write an article for a medical journal about these 2 substudies. The students will be a coauthor on these manuscripts.
Contact
Dr. Angelique de Man: ame.deman@amsterdamumc.nl
Dr. Harm-Jan de Grooth: h.degrooth@amsterdamumc.nl
Dr. Harry Gelissen: h.gelissen@amsterdamumc.nl
Estimation of micronutriet status in ICU patients
Micronutrient status, essential for metabolic, antioxidant and immune functions, is mostly estimated by plasma concentrations. These are frequently decreased (up to 90%!) in ICU-patients due to real losses through bodily fluids or increased metabolic use and/or apparent deficiencies caused by altered protein binding, dilution or redistribution due to inflammation. Therefore, they probably do not adequately reflect body status. There is no reliable correction factor for inflammation. Micronutrient supplementation in patients without a real deficiency may even be harmful. For example, in certain circumstances vitamins C and E may destroy the normal homeostatic immune equilibrium by upregulating synthesis of pro-inflammatory cytokines. Measurements in erythrocytes or leucocytes could be a better estimate of micronutrient status in ICU-patients and could be used for personalized supplementation. If intracellular concentrations turn out to be normal, supplementation may not be necessary and even be disadvantageous for patients.
Research aims:
- To measure simultaneously plasma and intracellular concentrations (both in erythrocytes and leucocytes) of critical micronutrients (vitamin B1, B6, B11, C, D, E, zinc and selenium) in 20 ICU-patients with a prolonged ICU-stay on day 1, 3, 5 and 7 of ICU-stay and in 20 healthy volunteers (2 random samples).
- To correlate plasma and intracellular concentrations of micronutrients with biomarkers of inflammation (CRP as biomarker of acute inflammation, α-1 acid glycoprotein as more reliable biomarker of inflammation during convalescence period), prealbumin as biomarker of nutritional status, and severity of organ dysfunction (DSOFA-score).
The student will write the study protocol for the clinical study and the student will assist in the development of the intracellular measurements in the Reinier de Graaf hospital in Delft. So, the student will learn a substantial amount of laboratory skills and will work mostly at the Reinier de Graaf hospital.
Contact
Dr. Angelique de Man: ame.deman@amsterdamumc.nl
Department of Physiology
Disease mechanisms in hypertrophic cardiomyopathy
Hypertrophic cardiomyopathy is frequently caused by mutations in genes encoding sarcomere proteins. Our group defines pathomechanisms which are triggered by the sarcomere gene mutation, and studies which additional disease factors (gene variants, stressors) cause disease. We test specific compounds which may delay and/or reverse cardiac dysfunction and remodeling.
Techniques: protein analyses (electrophoresis, gel stainings, western blot), histological analyses/microscopy, functional studies (single cell, engineered heart tissue, endothelial cell-cardiomyocyte cross-talk).
Contact
Prof. Jolanda van der Velden: j.vandervelden1@amsterdamumc.nl
Dr. Diederik Kuster: d.kuster@amsterdamumc.nl
Vascular integrity and endothelial cells
We study the molecular basis of vascular integrity. The research focus is on endothelial cells, the cells that line all blood vessels, and the machinery which controls their cell-cell contacts. This relates to control of cytoskeletal dynamics and protein degradation. Key proteins we are interested in are RhoGTPases and the enzymes that regulate their function. Our research combines biochemical and biophysical techniques with protein expression studies and high-resolution imaging of live endothelial cells.
Techniques: Endothelial cell isolation and culture; Western blotting; immunoprecipitation; cell transfection; siRNA studies; confocal microscopy; superresolution imaging; live cell imaging; expression of fluorescent proteins; biochemical assays for protein ubiquitylation; assays for endothelial integrity and vascular leakage; 2D and 3D flow models.
Contact
Prof. Peter Hordijk: p.hordijk@amsterdamumc.nl
Dr. Igor Kovacevic: i.kovacevic@amsterdamumc.nl
Long non-coding RNAs in cardiovascular disease
Most of the genome is transcribed in RNA, but only a fraction actually codes for protein. Our group studies the role of the so-called non-coding RNAs in cardiovascular biology. We particularly focus on long non-coding RNAs that are regulated during aging. We aim to unravel how individual non-coding RNAs regulate cardiovascular function, with the aim to identify non-coding RNAs that can be targeted therapeutically.
Techniques: Quantitative (real-time) PCR, RNA pulldown, RNA immunoprecipitation, cloning, deep sequencing analysis, advanced microscopy, siRNA transfection, gapmeR transfection, lentiviral overexpression, CRISPR-dCas9 overexpression tools.
Contact
Prof. Reinier Boon: r.a.boon@amsterdamumc.nl
Department of Molecular Cell Biology and Immunology
Targeting Immunometabolism to improve macrophage function and disease outcome
Our lab is interested in how metabolic pathways regulate macrophages. By targeting metabolic enzymes and pathways in macrophages, we aim to improve their functions and disease outcome, particularly focussing on cardiovascular diseases and cancers. To do so, we use a combination of human and mouse cellular and molecular models, in vivo approaches and validation in patient biopsies. We are especially interested in how immunometabolites control inflammation and regulate disease progression. By unravelling key questions in macrophage immunometabolism, our overall goal is to demonstrate whether and how targeting macrophage metabolism could be used for future therapy.
Techniques: metabolic profiling (including Seahorse flux analysis), functional screening, human and mouse primary cell culture, flow cytometry (FACS), bioinformatics.
Contact
Dr. Jan Van den Bossche: j.vandenbossche@amsterdamumc.nl
Department of Pathology
Viral myocarditis and sudden death
Viral myocarditis (VM) is an inflammatory disease of the heart that is associated with acute and chronic heart failure and also with sudden death and arrhythmias. Previous studies have shown that the myocardial inflammatory infiltrate associates with sudden death. In mouse models of VM as well as patient material we want to investigate how the local (heart) and systemic (blood, spleen and bone marrow) inflammatory responses associate with sudden death through cardiac arrhythmias and myocardial infarction.
Techniques: Echocardiography of heart function and ECG of conscious in VM mice; Tissue analysis via (immuno)histochemistry immunofluorescence, Tissue/cell culture, Flow cytometry.
Contact
Dr. Paul Krijnen: paj.krijnen@amsterdamumc.nl