In vivo microvascular endothelial cell pharmacology
Contact: Ingrid Molema
Endothelial cells in the smallest blood vessels in the body, the capillaries and postcapillary venules, are essential players in many diseases and nowadays accepted as important pharmacological targets to halt disease initiation/progression. Diseases under study are inflammatory processes in various (shock) conditions and cancer. Understanding the behavior of the endothelial cells in the microvascular segments in health and disease is a first step toward the design of effective therapeutic intervention strategies, the second step is to unravel the effects of drugs on these cells in their organ niche. Since endothelial cells show a major transcriptome drift after isolation from a particular organ and subsequent in vitro culture, it is of major importance to study these processes in the in vivo context. Besides focusing on the endothelial cells themselves we also take the behavior of the cells that make up the microenvironment of the microvascular segments into account.
The pathophysiology and mechanisms of SHOCK-mediated organ failure
Every day, critically ill patients in ICUs worldwide develop failure of vital organs usually as a result of infection (sepsis) or injury (trauma or surgery). This so called multiple organ dysfunction syndrome (MODS) leads to increased mortality among ICU patients. If patients survive MODS, their increased morbidity and mortality persists long after their ICU stay. As yet, no drugs are available to prevent or treat MODS.
The Shock research group is a multidisciplinary group within the University Medical Center Groningen (UMCG) comprising of clinician scientists and basic researchers from the Dept. of Critical Care and the EBVDT Research group. Our translational research is dedicated to understanding the pathophysiology and mechanisms of SHOCK-mediated organ failure in order to improve the clinical care of critically-ill patients.
Research Focus includes:
Immunogenesis and pathogenesis ANCA-mediated vasculitis
Contact: Peter Heeringa
Anti-neutrophil cytoplasmic autoantibody (ANCA)-associated small vessel vasculitides are rare, but life-threatening, systemic inflammatory diseases that affect small-to medium-sized blood vessels. Patients suffering from this disease have circulating autoantibodies that are directed against enzymes present in the neutrophils: myeloperoxidase or proteinase 3. Although multiple organs can be affected, the lungs and kidneys are often involved. Involvement of the kidneys results in crescentic glomerulonephritis (=inflammation of the blood filtering units in the kidney, the glomeruli). Increasing clinical and experimental evidence indicates that ANCA are causally involved in disease pathogenesis, yet, the exact mechanism of disease initiation and progression is still unknown. The aim of this research is to gain new insights into the pathogenesis of ANCA vasculitis and to identify key pathways and mediators involved in disease progression.
Development of targeted liposomal delivery systems for improved siRNA delivery to diseased endothelium.
Gene silencing by siRNA is a powerful technique with a potential for pharmacological application in the clinic. It is capable of knocking down targets in various diseases in vivo, including in hypercholesterolaemia, liver cirrhosis, hepatitis B virus infection (HBV), and cancer. Furthermore, siRNA technology enables the generation of cell specific, gene specific knock out animal models to mimic human diseases. We have designed and patented a system with superior intracellular release characteristics for systemic application of siRNA called SAINT-O-Somes, In addition to SAINT-O-Somes, our laboratory developed a non-liposomal, lipid-based targeting device for siRNA delivery, so-called SAINTargs, which also efficiently and specifically delivers siRNA into endothelial cells.
The aim of this research is to further develop our targeting systems in order to maximize in vitro and in vivo efficacy of siRNA delivery and gene knockdown in inflamed endothelial cells as well as endothelial cells that engage in angiogenesis.