Research team
Expertise
Biological markers of affective disorders. Analysis of drugs and metabolites concentrations in biological matrices (serum, plasma, urine).
Support maintenance scientific equipment (Medical Biochemistry).
Abstract
This project represents a research contract awarded by the University of Antwerp. The supervisor provides the Antwerp University research mentioned in the title of the project under the conditions stipulated by the university.Researcher(s)
- Promoter: De Meester Ingrid
- Promoter: Hendriks Dirk
Research team(s)
Project type(s)
- Research Project
Carboxypeptidase U - a new drug target for the improvement of treatment in acute ischemic stroke.
Abstract
Thrombolysis with tissue plasminogen activator remains the only approved pharmacological treatment for acute ischemic stroke, AIS. Besides the narrow therapeutic time window, its use is limited by its efficacy: in up to 50% of the treated patients, timely recanalization is not achieved. Moreover, administration involves serious side effects such as intracranial hemorrhage and neurotoxicity. Consequently, the search for new agents for improvement of AIS treatment is urgently needed. Research has demonstrated that the enzyme carboxypeptidase U (CPU, TAFIa) is an important player in thrombus lysis. After activation from its precursor proCPU, the released CPU is able to potently attenuate fibrinolysis. Consequently, inhibition of CPU activity is a novel approach to enhance fibrinolysis. We want to explore the involvement of this enzyme in AIS in more detail. The usefulness of CPU as a diagnostic marker to discriminate ischemic from hemorrhagic stroke and the relationship of CPU with clinical outcome and thrombolytic treatment efficacy will be investigated. We plan to optimize the Thrombodynamics assay in order to assess the effect of CPU-inhibition on clot lysis during thrombolysis. Furthermore, in a preclinical setting, we will evaluate the effect of CPU inhibition in an experimental stroke model in rats. This research will provide essential information on the role of the CPU system and the usefulness of CPU inhibitors as potentially efficient and safer treatment of AIS.Researcher(s)
- Promoter: Hendriks Dirk
- Co-promoter: Lambeir Anne-Marie
- Fellow: Mertens Joachim
Research team(s)
Project type(s)
- Research Project
Carboxypeptidase U - a new drug target for the improvement of treatment in acute ischemic stroke.
Abstract
Thrombolysis with tissue plasminogen activator remains the only approved pharmacological treatment for acute ischemic stroke, AIS. Besides the narrow therapeutic time window, its use is limited by its efficacy: in up to 50% of the treated patients, timely recanalization is not achieved. Moreover, administration involves serious side effects such as intracranial hemorrhage and neurotoxicity. Consequently, the search for new agents for improvement of AIS treatment is urgently needed. Research has demonstrated that the enzyme carboxypeptidase U (CPU, TAFIa) is an important player in thrombus lysis. After activation from its precursor proCPU, the released CPU is able to potently attenuate fibrinolysis. Consequently, inhibition of CPU activity is a novel approach to enhance fibrinolysis. We want to explore the involvement of this enzyme in AIS in more detail. The usefulness of CPU as a diagnostic marker to discriminate ischemic from hemorrhagic stroke and the relationship of CPU with clinical outcome and thrombolytic treatment efficacy will be investigated. We plan to optimize the Thrombodynamics assay in order to assess the effect of CPU-inhibition on clot lysis during thrombolysis. Furthermore, in a preclinical setting, we will evaluate the effect of CPU inhibition in an experimental stroke model in rats. This research will provide essential information on the role of the CPU system and the usefulness of CPU inhibitors as potentially efficient and safer treatment of AIS.Researcher(s)
- Promoter: Hendriks Dirk
- Co-promoter: Lambeir Anne-Marie
- Fellow: Mertens Joachim
Research team(s)
Project type(s)
- Research Project
The role of carboxypeptidase U in atherosclerosis and its thrombotic complications.
Abstract
In the first stage of the project we will extend the knowledge about assays for the measurement of CPU, i.e. the clot lysis assay and an ultrasensitive activity-based method. Next we will use these techniques to investigate the role of CPU in patients with acute myocardial infarction. A third objective is to explore the localization of CPU in atherosclerotic plaques and thrombi. Finally, we will evaluate the role of CPU in a novel plaque rupture model. Investigating the role of CPU in atherosclerosis and its clinical manifestations may open new approaches for plaque stabilising therapies and treatment of acute ischemic syndromes.Researcher(s)
- Promoter: Hendriks Dirk
- Co-promoter: Lambeir Anne-Marie
- Fellow: Leenaerts Dorien
Research team(s)
Project type(s)
- Research Project
The role of carboxypeptidase U in atherosclerosis and its thrombotic complications.
Abstract
In the first stage of the project we will extend the knowledge about assays for the measurement of CPU, i.e. the clot lysis assay and an ultrasensitive activity-based method. Next we will use these techniques to investigate the role of CPU in patients with acute myocardial infarction. A third objective is to explore the localization of CPU in atherosclerotic plaques and thrombi. Finally, we will evaluate the role of CPU in a novel plaque rupture model. Investigating the role of CPU in atherosclerosis and its clinical manifestations may open new approaches for plaque stabilising therapies and treatment of acute ischemic syndromes.Researcher(s)
- Promoter: Hendriks Dirk
- Co-promoter: Lambeir Anne-Marie
- Fellow: Leenaerts Dorien
Research team(s)
Project type(s)
- Research Project
HPLC analyses in Mood Disorder Project.
Abstract
This project represents a formal service agreement between UA and on the other hand Vestre Viken Hospital Trust. UA provides Vestre Viken Hospital Trust research results mentioned in the title of the project under the conditions as stipulated in this contract.Researcher(s)
- Promoter: Hendriks Dirk
Research team(s)
Project type(s)
- Research Project
HPLC analyses in activation of the kynurenine pathway in the acute phase of stroke, and its role in depression and fatigue following stroke.
Abstract
This project represents a formal research agreement between UA and on the other hand a private institution. UA provides the private institution research results mentioned in the title of the project under the conditions as stipulated in this contract.Researcher(s)
- Promoter: Hendriks Dirk
Research team(s)
Project type(s)
- Research Project
Carboxypeptidase M, substrates and ligands.
Abstract
The aim of the project is to identify interaction partners of human carboxypeptidase M (CPM). The research plan has two components. On the one hand we study the interaction with bioactive peptides that are substrates for the carboxypeptidase enzymatic activity. On the other hand we investigate a potential role of this membrane bound protein in cell-cell interactions, extracellular matrix interactions and cell migration.Researcher(s)
- Promoter: Lambeir Anne-Marie
- Co-promoter: Hendriks Dirk
- Fellow: Denis Catherine
Research team(s)
Project type(s)
- Research Project
Carboxypeptidase U: a metallocarboxypeptidase with a distinct role in haemostasis and a possible risk factor for thrombotic disease.
Abstract
Carboxypeptidase U (CPU), also referred to as active Thrombin-Activatable Fibrinolysis Inhibitor (TAFIa), is a recently discovered attenuator of the fibrinolytic rate and is considered to be the molecular link between coagulation and fibrinolysis. The measurement of active CPU in plasma is associated with mayor pitfalls. It is our goal to develop a sensitive and selective assay allowing us to determine limited amounts of CPU in circulation. In a second phase, this assay is being used to identify patient groups (MI, PE, DVT, ischemic stroke, sepsis, ¿) were the CPU system is being activated and thus could affect the outcome or severity of the pathology.Researcher(s)
- Promoter: Hendriks Dirk
- Fellow: Heylen Evelien
Research team(s)
Project type(s)
- Research Project
Carboxypeptidase M, substrates and ligands.
Abstract
The aim of the project is to identify interaction partners of human carboxypeptidase M (CPM). The research plan has two components. On the one hand we study the interaction with bioactive peptides that are substrates for the carboxypeptidase enzymatic activity. On the other hand we investigate a potential role of this membrane bound protein in cell-cell interactions, extracellular matrix interactions and cell migration.Researcher(s)
- Promoter: Lambeir Anne-Marie
- Co-promoter: Hendriks Dirk
- Fellow: Denis Catherine
Research team(s)
Project type(s)
- Research Project
Carboxypeptidase U: a metallocarboxypeptidase with a distinct role in haemostasis and a possible risk factor for thrombotic disease.
Abstract
Carboxypeptidase U (CPU), also referred to as active Thrombin-Activatable Fibrinolysis Inhibitor (TAFIa), is a recently discovered attenuator of the fibrinolytic rate and is considered to be the molecular link between coagulation and fibrinolysis. The measurement of active CPU in plasma is associated with mayor pitfalls. It is our goal to develop a sensitive and selective assay allowing us to determine limited amounts of CPU in circulation. In a second phase, this assay is being used to identify patient groups (MI, PE, DVT, ischemic stroke, sepsis, ¿) were the CPU system is being activated and thus could affect the outcome or severity of the pathology.Researcher(s)
- Promoter: Hendriks Dirk
- Fellow: Heylen Evelien
Research team(s)
Project type(s)
- Research Project
Carboxypeptidase M, substrates and ligands.
Abstract
The aim of the project is to identify interaction partners of human carboxypeptidase M (CPM). The research plan has two components. On the one hand we study the interaction with bioactive peptides that are substrates for the carboxypeptidase enzymatic activity. On the other hand we investigate a potential role of this membrane bound protein in cell-cell interactions, extracellular matrix interactions and cell migration.Researcher(s)
- Promoter: Lambeir Anne-Marie
- Co-promoter: Hendriks Dirk
- Fellow: Denis Catherine
Research team(s)
Project type(s)
- Research Project
Molecular characterisation of carboxypeptidase M, an extracellular membrane-bound peptidase involved in the tissue-specific response toward biologically active peptides.
Abstract
Carboxypeptidase M (CPM) is a cell-surface bound carboxypeptidase which removes C-terminal basic aminoacids from bioactive peptides. CPM has been reported to be distributed in many organs and fluids. CPM is also present on immunological and inflammatory cells. However, a physiological role of CPM in these tissues has not yet been clearly defined. Commonly, it is accepted that CPM can be a player in the processing or inactivation of peptide hormones, growth factors, inflammatory important peptides, et cetera. As there is very little knowledge of the molecular properties of CPM, we aim to systematically characterise the catalytic mechanisme and substrate specificity of CPM. These investigations must allow to differentiate between the various carboxypeptidases, specifically concerning the substrate specificity. Carboxypeptidase U (CPU) inhibitors are currently under clinical investigation as adjuvans in the fibrinolytic therapy. The importance of studying the selectivity of the CPU inhibitors with regard to other carboxypeptidases is self-evident. In this context, CPM is particulary important because it is constitutionally expressed in many tissues. In the first phase of our project, CPM will be cloned, expressed and purified. A comparative study of the recombinant and natural enzyme will be performed. We wish to study the different elements of the catalytic proces using enzymological methods. The substrate specificity of CPM will be studied using site-directed mutagenesis. In the second phase, we aim to identify naturally occuring substrates of CPM in tissue extracts (proteomics analysis). Extracted polypeptides will be fractionated and analysed for the presence of substrate (LC-MS). The enzyme kinetics of these substrates will be studied in vitro. A last aim is to set up a database of CPM values in normal and clinical samples. The results of our study can be used in the development of new CPU inhibitors. New therapeutic strategies can be proposed if the involvement of CPM in inflammation is confirmed. The possibility of administering therpeutic peptides as aerosol is under research. The presence of CPM on type I alveolar cells can influence the absorption and pharmacokinetics of these drugs.Researcher(s)
- Promoter: Lambeir Anne-Marie
- Co-promoter: Hendriks Dirk
- Fellow: Deiteren Kathleen
Research team(s)
Project type(s)
- Research Project
Novel mechanisms in the physiological and pathophysiological regulation of the fibrinolytic pathway.
Abstract
The current work will focus on exploring the function of the novel enzyme carboxypeptidase U and its role in the fibrinolysis. We will also investigate if the proCPU/CPU system is involved in the activation or inactivation of other physiological substrates bearing a C-terminal basic amino-acid.Researcher(s)
- Promoter: Hendriks Dirk
- Fellow: Willemse Johan
Research team(s)
Project type(s)
- Research Project
Does the plasma proCPU (TAFI) concentration modulate the clinical expression of hereditary diseases of primary haemostasis ?
Abstract
Patients presenting with non thrombocytopenic mucocutaneous haemorrhages (MHC) of hereditary nature are usually difficult to diagnose. It is widely accepted that most of these patients have a mild disorder of primary haemostasis, most frequently, type 1 von Willebrand disease (vWD) and platelet aggregation/ secretion defects (PASD). However, many patients presenting with clinically significant MCH have no demonstrable alterations in plasma von Willebrand factor and ex vivo platelet function. On the other hand, it is common to observe abnormalities in these tests in subjects with no abnormal haemorrhages. These observations suggest that the pathogenesis of the bleeding disorder in many of these patients is still unknown. We hypothesize that the concentration of other haemostatic factors influence or modulate the clinical expression of MCH, the bleeding symptoms resulting from the interactions and final balance among pro- and anticoagulant factors. Specifically, we propose that the overall activity of the fibrinolytic system is enhanced in patients as compared with controls, and that this hyperactivity contributes to bleeding. Among the determinants of fibrinolytic activity, in this project we propose to analyze the influence of plasma procarboxypeptidase U (proCPU, TAFI) levels and activity in patients consulting for MCH. Carboxypeptidase U, a recently discovered exopeptidase, circulates in plasma as an inactive proform, proCPU. Thrombin activates CPU, and the active form attenuates fibrinolysis by cleaving C-terminal lysine residues exposed on partially degraded fibrin by the action of plasmin. Theoretically, the lower the CPU activity, the higher the rate of fibrinolysis and thus the speed of fibrin clot degradation and removal. Thus, severely suppressed proCPU activation or concentration might be associated with a tendency to bleed, and accordingly, we propose that patients with MCH have a lower proCPU concentration and/or activity. In this context, low plasma proCPU would be considered a risk factor for haemorrhages and, as such, would potentiate the bleeding tendency in patients with vWD and PASD and high plasma proCPU would attenuate their bleeding tendency. Moreover, we hypothesize that patients with MCH, but with no specific diagnosis and those with prolonged bleeding time have lower plasma levels of proCPU than non-bleeder controls and patients with normal bleeding time.The prospective, controlled study, will be performed in patients consulting for MCH, which will be classified in different diagnostic categories (vWD, PASD, vWD+PASD, and patients with no specific diagnosis). Age and sex-matched healthy individuals, with no history of personal or familial bleeding will be used as controls. In all of them, plasma proCPU will be measured by antigenic and functional assays.Researcher(s)
- Promoter: Hendriks Dirk
Research team(s)
Project type(s)
- Research Project
Novel mechanisms in the physiological and pathophysiological regulation of the fibrinolytic pathway.
Abstract
The current work will focus on exploring the function of the novel enzyme carboxypeptidase U and its role in the fibrinolysis. We will also investigate if the proCPU/CPU system is involved in the activation or inactivation of other physiological substrates bearing a C-terminal basic amino-acid.Researcher(s)
- Promoter: Hendriks Dirk
- Fellow: Willemse Johan
Research team(s)
Project type(s)
- Research Project
Development of new fixating entities (NFE's) for tissue processing.
Plasma procarboxypeptidase U: a novel regulator of fibrinolysis and potential risk factor for cardiovascular disease.
Abstract
Carboxypeptidase U (CPU, EC 3.4.17.20) belongs to the group of the basic carboxypeptidases. These enzymes cleave basic amino acid (lysine or arginine) from the C-terminus of the peptide chain. Carboxypeptidase U circulates in blood as an inactive zymogen,procarboxyppetidase U. During the process of coagulation and fibrinolysis it is converted to its active form, carboxypeptidase U. The physiological function of CPU is probably restricted to the coagulation-fibrinolysis system where it is involved in regulating the rate of fibrin lysis. The velocity of fibrinolysis is determining for the balance between coagulation and fibrinolysis. Disturbance of this equilibrium could result either in thrombosis or haemorrhage. Whether the proCPU plasmaconcentration plays a significant role and thus can be regarded as risk factor for cardiovascular diseases, remains to be investigated.Researcher(s)
- Promoter: Hendriks Dirk
- Fellow: Leurs Judith
Research team(s)
Project type(s)
- Research Project
Plasma procarboxypeptidase U: a novel regulator of fibrinolysis and potential risk factor for cardiovascular disease.
Abstract
Carboxypeptidase U (CPU, EC 3.4.17.20) belongs to the group of the basic carboxypeptidases. These enzymes cleave basic amino acid (lysine or arginine) from the C-terminus of the peptide chain. Carboxypeptidase U circulates in blood as an inactive zymogen,procarboxyppetidase U. During the process of coagulation and fibrinolysis it is converted to its active form, carboxypeptidase U. The physiological function of CPU is probably restricted to the coagulation-fibrinolysis system where it is involved in regulating the rate of fibrin lysis. The velocity of fibrinolysis is determining for the balance between coagulation and fibrinolysis. Disturbance of this equilibrium could result either in thrombosis or haemorrhage. Whether the proCPU plasmaconcentration plays a significant role and thus can be regarded as risk factor for cardiovascular diseases, remains to be investigated.Researcher(s)
- Promoter: Hendriks Dirk
- Fellow: Leurs Judith
Research team(s)
Project type(s)
- Research Project
Plasma procarboxypeptidase U : a novel risk factor for cardiovascular disease ?
Abstract
Procarboxypeptidase U (proCPU) is a novel proenzyme found in human plasma which was first discovered by our group. The active form, carboxypeptidase U (CPU) retards the rate of fibrinolysis through its ability to cleave C-terminal lysine residues on fibrin partially degraded by plasmin. We developed assays to measure the proCPU concentration in plasma and will study patient groups with increased thrombo-embolic risk to determine whether a high proCPU concentration is a risk factor for developing thrombo-embolic disease.Researcher(s)
- Promoter: Hendriks Dirk
- Fellow: Leurs Judith
Research team(s)
Project type(s)
- Research Project
Abstract
Researcher(s)
- Promoter: Hendriks Dirk
- Co-promoter: Scharpe Simon
Research team(s)
Project type(s)
- Research Project
Structure activity study of novel bradykinin modulating peptidases.
Abstract
The physiologically nonapeptide bradykinin can be cleaved by a number of proteases. Activation by plasmin, thrombin or trypsin results in the formation of carboxypeptidase which is able to transform bradykinin into des-Arg9-bradykinin and act as a novel kininase.Researcher(s)
- Promoter: Hendriks Dirk
- Fellow: Goossens Filip Ja
Research team(s)
Project type(s)
- Research Project
Abstract
Researcher(s)
- Promoter: Hendriks Dirk
- Co-promoter: Scharpe Simon
Research team(s)
Project type(s)
- Research Project
Role of carboxy- and aminoterminal amino acids in the biological processing of peptides.
Abstract
A new basic procarboxypeptidase - procarboxypeptidase U - was found to be present in human plasma. Upon activation by plasmin or thrombin, active procarboxypeptidase U is able to interfere in the process of coagulation, fibrinolysis, complement activation and the kallikrein/kinin system by removal of C-terminal lysine and arginine residues from a number of potent peptides.Researcher(s)
- Promoter: Hendriks Dirk
- Fellow: Schatteman Katinka A M
Research team(s)
Project type(s)
- Research Project
Role of carboxy- and aminoterminal amino acids in the biological processing of peptides.
Abstract
A new basic procarboxypeptidase - procarboxypeptidase U - was found to be present in human plasma. Upon activation by plasmin or thrombin, active procarboxypeptidase U is able to interfere in the process of coagulation, fibrinolysis, complement activation and the kallikrein/kinin system by removal of C-terminal lysine and arginine residues from a number of potent peptides.Researcher(s)
- Promoter: Hendriks Dirk
- Fellow: Schatteman Katinka A M
Research team(s)
Project type(s)
- Research Project
Computer aided design and synthesis of inhibitors of dipeptidylpeptidase IV.
Abstract
T-lymphocytic dipeptidylpeptidase IV plays an important role in the activation of the immune system. Inhibitors of this enzyme could play an important role in understanding the role of growth factors and cytokines.Researcher(s)
- Promoter: Hendriks Dirk
Research team(s)
Project type(s)
- Research Project
Human plasma carboxypeptidase U : study of its activation, plasminogen binding and role in the fibrinolytic system.
Abstract
Carboxypeptidase U is a recently discovered basic carboxypeptidase which circulates in human plasma as an inactive precursor enzyme. Due to its affinity for plasminogen, this enzyme could play an important role in the fibrinolytic system.Researcher(s)
- Promoter: Hendriks Dirk
Research team(s)
Project type(s)
- Research Project