Research team

Pathophysiology

Expertise

- Quantitative bone histomorphometry - Histomorphometry /histology soft tissues - Immunohistochemistry - Laser capture microdissection - Real-time RT PCR - µ-tomography (in coll. Laboratory of Microtomography) - Synchrotron-based X-ray fluorescence/diffraction (in coll ESRF, Grenoble) - Analysis of heavy metals (atomic absorption spectrometry) - Cell culture (osteoblasts, vascular smooth muscle cells, kidney cells, parathyroid cells) - Animal models (vascular calcification, renal osteodystrophy, chronic/acute renal failure, nephrocalcinosis, osteoporosis) - Early renal markers - Proteomics

Cell death detection platform. 01/01/2020 - 31/12/2021

Abstract

We request funding for two basic infrastructure equipment to measure cell death along any other biochemical parameter that is crucial to determine the mode of cell death such as caspase activation, reactive oxygen species, calcium, mitochondrial membrane potential, lysosomal leakage and lipid peroxidation: 1) FLUOstar® Omega plate reader with atmospheric control unit and 2) BD Accuri C6 Plus personal flow cytometer. These two instruments are perfectly complementary, while the Fluostar provides average values measured on cell populations seeded in any plate up to 384-well plates, the Accuri analyzes at the single cell level allowing to detect heterogenous responses. If the transition from Pathophysiology lab (headed by Patrick D'Haese until 2020) to Cell Death and Inflammation research lab (headed by Tom Vanden Berghe from 2020 onwards) is to proceed smoothly, the investment in this basic but crucial equipment to analyze cell death and related biochemical features is highly needed. Investment in the cell death platform at UAntwerp will boost the recently initiated collaborations in the field of cell death research at UAntwerp. Cell death research is highly present but scattered within the Faculties of FBD and GGW, therefore we initiated monthly sessions of the Cell Death Hot Talks (supported by the OEC Infla-Med). These sessions will (i) increase the exchange on ongoing cell death research, (ii) lead to sharing tools and (iii) boost potential collaborations. Along this line of sharing cell death related expertise and tools, there is a high need to setup a platform to measure and type the mode of cell death within the faculties of FBD and GGW. This investment fits well in the long-term strategic plan in which cell death is one of the four research clusters within the Department of Biomedical Sciences. Moreover, the cell death platform could be instrumental as a steppingstone to make cell death an Emerging Frontline Research Domain.

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Research team(s)

Metformin as RenoProtector in NonDiabetic Patients with Progressive Chronic Kidney Disease (CKD stages 2, 3A and 3B): a multicentre, practice-oriented, repurposing, double-blind, placebo-controlled, randomized clinical trial (RenoMet) 26/02/2019 - 31/12/2024

Abstract

This multi-centre, practice-oriented, repurposing, double-blind, placebo-controlled, randomized clinical trial evaluates the effect of metformin treatment on the progression of chronic renal failure

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Toxin induced lysosomal storage disease: a new etiological, mechanistic, diagnostic and prognostic paradigm for the worldwide increasing prevalence of agrochemical-associated nephropathy. 01/01/2019 - 31/12/2022

Abstract

Chronische nierinsufficiëntie (CKD) is een klinische conditie gekenmerkt door the progressief verlies van functionele renale massa. Gedurende de laatste 20 jaar werd in een aantal agrarische gemeenschappen een continue stijging van patiënten met chronische nierinsufficiëntie waargenomen, die wereldwijd miljoenen menen treft. De ziekte werd Chronische Interstitiële Nefritis in Agrarische Culturen genoemd (CINAC). Daar waar chronische dehydratie door sommigen als de voornaamste oorzaak van de aandoening werd voorgesteld, is er momenteel meer en meer evidentie voor blootstelling aan agrochemicaliën als belangrijkste oorzaak. De oorzakelijke oorzaak en onderliggende mechanismen blijven echter nog steeds een onderwerp van discussie.

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In vitro and in vivo research to investigate the role of the Wnt/beta-catenin signaling cascade in vascular calcification and the bone-vascular axis. 01/10/2018 - 30/09/2021

Abstract

The calcification paradox is seen in chronic kidney disease (CKD) and osteoporosis patients and refers to the occurrence of a bone pathology characterized by a disturbed bone turnover/mineralisation in combination with calcification of the medial layer of the vessel wall; i.e. arteriosclerosis. This process of vascular calcification, which shares many similarities to bone development, is a rapidly progressive aspect of cardiovascular disease and is linked to increased morbidity and mortality particularly in CKD patients. As safe therapies to treat these mineralisation defects are urgently needed, this topic raised great interest during the last years. A pathway that might clarify the co-occurrence of mineralisation defects at the level of bone and vasculature is the Wnt/beta-catenin signalling pathway. It is known that this pathway regulates bone formation, however, its role in vascular calcification is less clear. The most obvious strategy in elucidating the potential (patho-)physiological roles of this cascade is by studying the functions of sclerostin and Dickkopf-related protein 1 (DKK1), both well-known inhibitors of the Wnt/beta-catenin signalling. Additionally, concerns are raised against the cardiovascular safety of anti-Scl and anti-DKK1 antibodies which are currently tested in clinical trials as a treatment for osteoporosis. Therefore, clarifying the mechanisms underlying this paradox is essential for the development of safe preventive and therapeutic treatments.

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Research team(s)

Identification of signaling pathways as druggable targets to combat vascular stiffness, a life threatening vascular pathology with high impact on multiple organs. 01/01/2018 - 31/12/2021

Abstract

Vascular stiffening is a growing epidemic associated with a high risk of cardiovascular disease, and end organ-damage in kidney and brain. No effective therapies to combat this life threatening vascular pathology currently exist, which is largely due to the lack of knowledge on the underlying molecular mechanisms. Therefore, this project aims to identify novel druggable targets which opens up new perspectives for discovery and evaluation of inventive therapies. Endothelial dysfunction and vascular calcification are well known pathological processes leading to vascular stiffness. Established mouse models of endothelial dysfunction and vascular calcification will therefore be used to identify the molecular signaling pathways responsible for vascular stiffness by means of a proteomic approach of arterial tissue. Additionally, we will explore the reciprocal relationship between endothelial dysfunction, vascular calcification and stiffness. As impaired autophagy has been suggested to play a role in vascular aging, this project will also focus on its role in vascular calcification and stiffness. To explore whether autophagy is a candidate target for future intervention studies, complementary in vivo studies will be performed that investigate the effect of both autophagy induction and defective autophagy on vascular calcification and stiffness. Broader ambitions of this project are to reduce the impact and lower the economic burden of vascular stiffness on society.

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CINAC, a major globally emerging chronic renal disease of unknown origin: unraveling the molecular mechanism and etiology to allow diagnostic tool development. 01/01/2018 - 31/12/2021

Abstract

In the last two decades, an increase is observed in the prevalence of a new form of chronic kidney disease in various countries around the world. A notable feature here is that it cannot be attributed to the common causes of CKD and is only diagnosed through aspecific criteria. The disease is primarily affecting young, male agricultural workers working in harsh conditions in hot tropical climates. Considering the epidemiological and histopathological findings in human biopsy material, this disease was named Chronic Interstitial Nephritis in Agricultural Communities (CINAC). The cause of CINAC remains unclear as there is no scientific consensus on a main causative agent. The histopathological phenotype is indistinguishable to that of patients' biopsies, treated with calcineurin inhibitors, suggesting CINAC might have a toxicological cause. In a preliminary study in our lab, biopsies from CINAC patients from Sri Lanka, El Salvador, and Portugal have been examined and they all showed an increase in the number of dysmorphic lysosomes and the shedding of cell fragments of affected cells. This histopathological phenotype suggests that the cellular fragments can be retrieved in, and isolated from, urine. From these isolated fragments, a protein analysis will be performed, possibly revealing the involvement of certain molecular pathways. Subsequently, a non-invasive diagnostic screening method can be developed. This can provide a first positive discriminator to diagnose this disease.

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The Measurement of Renal Markers. 01/07/2017 - 30/09/2021

Abstract

In this study it will be investigated to which extent exposure to depleted uranium during the Gulf War may result in renal damage. For the purpose of this a series of urinary markers of renal dysfunction will be measured

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Development of effective treatments for vascular media calcification, a major clinical issue in our ageing population. 01/01/2017 - 31/12/2021

Abstract

Vascular calcification or the deposition of calcium-phosphate crystals in the arteries has a severe impact on morbidity/mortality in elderly and patients with chronic kidney disease (CKD) and diabetes mellitus (DM) by inducing severe cardiovascular events. In our ageing society (CKD and DM are ageing diseases), treatment for vascular calcification is warranted. However, current therapies only consist of controlling risk factors and therefore effective therapies to prevent/cure vascular calcification are lacking. For this reason we aim to investigate new treatment strategies that directly inhibit arterial calcification in two ways (i) directly interfering with crystal formation in the vessel wall and (ii) directly targeting the predominant cells in arterial calcification; by targeting respectively cell receptor independent and dependent effects of extracellular nucleotides on the vascular calcification process. Treatments will not only be tested for their ability to prevent vascular calcifications but also to attenuate the progression of pre-existing calcifications as most patients present themselves with a given degree of vascular calcification. Since vascular calcification shares many features with the bone formation process it is furthermore important to test new therapies inhibiting vascular calcifications for negative effects on the bone. In conclusion, the aim of this project is to develop effective therapies for vascular calcification without side-effects on the bone

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Arterial stiffening as a common pathophysiological mechanism in cardiac and kidney failure and brain degeneration. 01/01/2017 - 31/12/2020

Abstract

The elasticity of the arterial wall is a physiologically elegant solution of nature for smoothing the pulsatile flow of blood from the heart to peripheral tissues. The loss of this elasticity during life is a consequence of pathophysiological alterations in the vessels eventually causing arterial stiffening. Emerging evidence demonstrates that arterial stiffness is an important driving force for multiple heart, kidney and brain pathologies (end-organ damage). Nevertheless, it is currently not clear which molecular pathways contribute to arterial stiffness and whether similar mechanisms link diverse end-organ pathologies. Therefore, the present proposal aims to investigate the following research questions in three work packages: Work package 1: Pathophysiological characterization of two mouse models of arterial stiffening and its relationship with end-organ damage. In this part of the project, we will characterize mouse models of two pathophysiological processes leading to arterial stiffness: endothelial dysfunction and extracellular matrix modification/calcification. Two appropriate mouse models, i.e. eNOS knockout mice and warfarin exposed mice will be examined in a longitudinal manner to investigate the time-dependent development of arterial stiffness and its relationship with end-organ damage (heart and kidney damage and brain degeneration). In a next step, a combined mouse model of arterial stiffness and cerebral beta-amyloid accumulation (cross breeding of one of the above models with APP23 transgenic mice) will be applied to explore whether arterial stiffness is able to enhance beta-amyloid accumulation in the brain, thereby promoting the development/progression of Alzheimer's disease. Techniques that will be used to measure arterial stiffness and end-organ damage include high-frequency ultrasound (Vevo2100), tonometry, pressure myography, immunohistochemistry and behavioral assessment of learning and cognition. Work package 2: What are the age-related molecular mechanisms that underlie arterial stiffness leading to end-organ damage? The second part of the project aims to unravel the (common) molecular pathway(s) that underlie the development of arterial stiffness and the end-organ damage by comparing protein expression/post-translational modification status in arteries, hearts, kidneys and brains originating from mice with and without arterial stiffening, using mass spectrometric isobaric mass-tag labeling proteomics (iTRAQ). We aim to investigate the age-dependent generation of potentially convergent pathological signaling processes, across the lifespan of mice, in stiffening arteries, damaged heart and kidney tissue and degenerating brain tissues. The search for potential common molecular pathway(s) ('disease signatures') underlying the development of arterial stiffness may allow the identification of new targets for the prevention or treatment of arterial stiffness and ensuing end-organ damage. Work package 3: How can arterial stiffness and subsequent end-organ damage be prevented or treated? The last work package will evaluate the efficacy of substances that potentially prevent or treat the development of arterial stiffness and the resulting end-organ damage, more in particular heart and kidney failure as well as beta-amyloid accumulation in the brain. Substances that will be tested include molecules that modulate new targets that were identified during the protein expression studies (WP2), affect endothelial dysfunction (NO-donor or guanylate cyclase activator), inhibit calcification (pyrophosphate) or stimulate autophagy (mTOR inhibitor). Taken together, this project aims to unravel the molecular processes involved in arterial stiffness that might lead to prevention and/or treatment of arterial stiffness and hence reduce the risk and severity of age-related heart and kidney damage and brain degeneration.

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Research team(s)

In vitro and in vivo research to investigate the role of the Wnt/betacatenin signalling cascade in the calcification paradox by targeting its most important inhibitors DKK1 and sclerostin. 01/10/2016 - 30/09/2018

Abstract

The calcification paradox is seen in chronic kidney disease (CKD) and osteoporosis patients and refers to the occurrence of a bone pathology characterized by a disturbed bone turnover/mineralisation in combination with calcification of the medial layer of the vessel wall; i.e. arteriosclerosis. This process of vascular calcification, which shares many similarities to bone development, is a rapidly progressive aspect of cardiovascular disease and is linked to increased morbidity and mortality particularly in CKD patients. As safe therapies to treat these mineralisation defects are urgently needed, this topic raised great interest during the last years. A pathway that might clarify the co-occurrence of mineralisation defects at the level of bone and vasculature is the Wnt/beta-catenin signalling pathway. It is known that this pathway regulates bone formation, however, its role in vascular calcification is less clear. The most obvious strategy in elucidating the potential (patho-)physiological roles of this cascade is by studying the functions of sclerostin and Dickkopf-related protein 1 (DKK1), both well-known inhibitors of the Wnt/beta-catenin signalling. Additionally, concerns are raised against the cardiovascular safety of anti-Scl and anti-DKK1 antibodies which are currently tested in clinical trials as a treatment for osteoporosis. Therefore, clarifying the mechanisms underlying this paradox is essential for the development of safe preventive and therapeutic treatments.

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Research team(s)

Modular confocal microscopy platform with light sheet illumination. 01/05/2016 - 30/04/2020

Abstract

The application concerns an innovative microscopy platform for visualizing cells, tissue specimen and living small model organisms in three dimensions at unprecedented speed and with excellent resolution and contrast. As a unique feature, the platform is equipped with a light-sheet module, which is based on an orthogonal configuration of laser-generated, micrometer-thin plane illumination and sensitive one-shot detection. Seamless integration with confocal modalities enables imaging the same sample from the micro- to the mesoscale. The device has a broad application radius in the neurosciences domain inter alia for studying neurodegeneration and -regeneration (e.g. whole brain imaging, optogenetics); but it also has direct utility in various other fields such as cardiovascular research (e.g. plaque formation and stability), plant developmental research (e.g. protein localization during plant growth) and ecotoxicology (e.g. teratogenicity and developmental defects in zebrafish). Furthermore, its modular construction will enable adaptation and targeted expansion for future imaging needs.

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Overcoming cell cycle arrest in injured kidneys: key to efficient renal regeneration. 01/01/2016 - 31/12/2019

Abstract

Arrest of the cell cycle at the G2/M stage of proliferating renal epithelial cells hampers repair of injured kidneys. The mechanism behind this is yet unknown. Here, we aim at identifying the major (dysregulated) signaling pathways determining cell cycle behavior in epithelial cells from injured murine kidneys and focus on DNA-methylation and microRNAs as potential therapeutic targets.

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Vascular calcification in chronic renal failure: optimization of alternative research models, evaluation of innovative treatments and further elucidation of the underlying mechanisms. 01/10/2015 - 11/06/2019

Abstract

Patients with chronic kidney disease (CKD) develop extensive vascular calcification (VC), the main cause of mortality. Today, treatment of CKD-induced VC consists of controlling hyperphosphatemia, however, the beneficial effect of phosphate binders is limited. This project will evaluate a new therapeutic approach implying the direct interference with the mineralization process in the vessel wall, independently of the causal factors involved. The effect of pyrophosphate (PPi), a molecule that directly inhibits the formation of calcium phosphate crystals, will be evaluated on the onset of VC as well as on pre-existing VC. In addition, we aim to investigate whether the efficiency of PPi can be improved by a tissue non-specific alkaline phosphatase inhibitor, a molecule that prevents the PPi breakdown, and if this novel therapy does not harm physiological bone mineralization. The second part will focus on the mechanisms of VC to explore new targets for inhibitor compounds. In vitro studies will be performed to find out whether the conversion of vascular cells towards bone-like cells during calcification can be stopped by use of RNAi to inactivate relevant proteins in this cellular process and, with regard to patient outcome, whether inhibition of this process influences calcification. Finally, the emerging role of the P2Y2 nucleotide receptor in VC will be studied in vivo. The current lack of treatment makes full elucidation of the molecular mechanisms of VC imperative.

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The role of sclerostin in vascular calcification and the calcification paradox: necessary research for development of safe therapies to treat mineralization defects in bone and vessels. 01/10/2015 - 30/09/2016

Abstract

Cardiovascular disease is responsible for a substantial part of mortality in patients with chronic kidney disease (CKD) or diabetes (also a cause of CKD). Vascular calcification (VC) is a rapidly progressive, prominent aspect of cardiovascular disease in these patients as well as in those with osteoporosis. Remarkably, pathological VC in these patient groups goes along with disturbed bone metabolism. This association is called the calcification paradox. Development of new, safe therapies to treat the mineralization defects in bone and vessels is urgently needed. Sclerostin (Scl) is a protein produced by bone cells (osteocytes), inhibiting bone formation and mineralization. VC is regulated similarly to that of developing bone: vascular smooth muscle cells (VSMC) transdifferentiate to cells with a bone-like phenotype and proteins involved in bone formation also regulate the development of VC. Scl expression has been found in VSMC during calcification and CKD patients with VC were observed to have higher serum Scl. The Laboratory of Pathophysiology was the first to find an association between increased serum Scl and decreased mortality in hemodialysis patients. Hence, it is not surprising that during the last years the potential role of Scl in vascular pathophysiology and the calcification paradox has received increasing interest. This project aims to elucidate the complex role of Scl in mineralistation defects of bone and vessels and their reciprocal effects onto each other -

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Medicinal Chemistry-Drug Discovery (ADDN). 01/01/2015 - 31/12/2020

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.

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INFLA-MED - Fundamental research in the pathophysiological processes of inflammatory diseases. 01/01/2015 - 31/12/2019

Abstract

The Infla-Med consortium performs fundamental research on the pathophysiological processes of inflammatory diseases (cardiovascular, gastrointestinal, renal and infectious disease) by using a multidisciplinary approach (pathophysiology, pharmacology, biochemistry and medicinal chemistry). The consortium is embedded within the research priorities 'Drug Research' and 'Infectious Diseases' of the University of Antwerp. Recently, the University of Antwerp assigned the Infla-Med consortium as Research Consortium of Excellence.

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The role of sclerostin in vascular calcification and the calcification paradox: necassary research for development of safe therapies to treat mineralization defects in bone and vessels. 01/01/2015 - 31/12/2018

Abstract

The current project aims to elucidate the role of sclerostin in vascular calcification and its complex relationship with disturbed physiological bone mineralization, in particular in patients with chronic kidney disease. This research is necassary in order to develop safe therapies for these pathologies.

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High-Frequency Ultrasound Imaging System Vevo 2100. 19/05/2014 - 31/12/2018

Abstract

This project represents a formal research agreement between UA and on the other hand the Hercules Foundation. UA provides the Hercules Foundation research results mentioned in the title of the project under the conditions as stipulated in this contract.

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Cell cycle control in proximal epithelial cells during progression of acute kidney injury to chronic kidney disease in vivo. 01/01/2013 - 31/12/2016

Abstract

The proposed project aims at getting profound molecular insight in cell cycle control of the proximal tubular epithelial cell in injured kidneys, an event recently recognized to play a critical role in the progression of acute kidney injury to chronic kidney disease.

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DNA methylation as a diagnostic and therapeutic target in chronic renal failure. 01/01/2012 - 31/12/2015

Abstract

This project represents a research agreement between the UA and on the onther hand IWT. UA provides IWT research results mentioned in the title of the project under the conditions as stipulated in this contract.

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Evaluation of intestinal oxalate and phosphate binding as a prevention strategy for renal calcifications. 01/01/2012 - 31/12/2013

Abstract

This project represents a research agreement between the UA and on the onther hand IWT. UA provides IWT research results mentioned in the title of the project under the conditions as stipulated in this contract.

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Investigation of intestinal oxalate binding as a new therapy for the prevention of nephrolithiasis/nephrocalcinosis. 01/10/2011 - 30/09/2015

Abstract

In the present project we will evaluate the usefulness of lanthanum carbonate in the prevention of hyperoxaluria/renal calcifications by investigating its capability to limit intestinal oxalate absorption and/or promote oxalate secretion.

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Characterization of the molecular pathways and their triggers underlying vascular calcification in chronic kidney disease and diabetes. 01/10/2011 - 30/09/2015

Abstract

In this project, the cell biological changes will be compared in calcified arteries from CKD patients and diabetics. To have a better insight into the molecular mechanisms underlying calcification in the arterial media and define the specific stimuli that regulate this process, the differential effects of inflammation versus phosphate on the transdifferentiation of medial smooth muscle cells will be investigated.

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The effect of silicon supplementation with orthosilicic acid and monomethyl silane triol on microarchitectural changes in rodent bones. 07/06/2011 - 30/04/2012

Abstract

This project represents a formal service agreement between UA and on the other hand MRC. UA provides MRC research results mentioned in the title of the project under the conditions as stipulated in this contract.

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Laser ablation solid sampling station for high-resolution inductively coupled mass spectrometer (LA-HR-ICP-MS). 22/07/2010 - 31/12/2014

Abstract

This project represents a formal research agreement between UA and on the other hand the Flemish Public Service. UA provides the Flemish Public Service research results mentioned in the title of the project under the conditions as stipulated in this contract.

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Epidemiological research into the prevalence and impact of (heavy) metals in the company Indaver. 30/03/2010 - 30/03/2012

Abstract

Several studies demonstrate that in case of combined exposure to heavy metals, metals can interact with each other and that the increased / decreased presence of a particular metal can affect the potential toxicity (both negative and positive) of another metal. Evidence for this is particularly found in animal research while the number of well-documented studies in humans is relatively limited. The objective of this research project is to measure the multi-element status of the entire working population of Indaver and to study the cumulative toxic or protective effect of moderately elevated multi-element exposure of heavy metals on relevant clinical and biochemical outcome parameters of the kidney.

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Impact of uremic retention solutes on vitamin D and bone metabolism. 01/01/2010 - 31/12/2013

Abstract

This research project aims to investigate to what extent protein-bound uremic toxins (a) affect the vitamin D micro-endocrine system in endothelial cells and (b) contribute to the pathogenesis and progression of ABD and vascular calcification in patients with CKD.

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Evaluation of intestinal oxalate and phosphate binding as a prevention strategy for renal calcifications. 01/01/2010 - 31/12/2011

Abstract

This project represents a research agreement between the UA and on the onther hand IWT. UA provides IWT research results mentioned in the title of the project under the conditions as stipulated in this contract.

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Screen certain samples on cadmium and lead accumulation in kidney, liver and bone. 15/07/2009 - 31/12/2012

Abstract

This project represents a formal service agreement between the parties Universiteit Antwerpen and Ministry of Health Sril Lanka. Universiteit Antwerpen provides MOH Sri Lanka research results on "Screen certain samples on cadmium and lead accumulation in kidney, liver and bone" under the conditions as stipulated in the present contract.

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Experimental research on the reversibility and prevention of nephrocalcinosis and nephrolithiasis. 01/01/2009 - 31/12/2012

Abstract

Goals of the project: 1. To investigate the bio-physicochemical mechanism of crystal clearance and the role of pH and inflammation therein. 2. To study the fundamental effects of acute hyperphosphatemia induced by therapeutic oral sodium phosphateintake on (i) the systemic regulators of the phosphate balance, (ii) the tubular epithelial phenotype and (iii) renal function, and investigate if these effects can be eliminated by limiting or inhibiting phosphate absorption in the intestine.

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Dipeptidyl peptidases beyond glucose homeostasis: from biochemistry to physiological importance. 01/01/2009 - 31/12/2012

Abstract

This project aims to better understand the effects of chronic dipeptidyl peptidase (DPP) inhibition on pre-defined aspects of cardiovascular, renal and bone (patho)physiology. Inhibitors with defined selectivity profiles will be developed as tools. Expression and inhibition of DPP4 and related peptidases will be studied on the molecular level, in cultured cells and in rat models of ischemia/reperfusion injury of heart and kidney.

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High Resolution Inductive Coupled Plasma Mass Spectrometer (HR-ICP-MS). 19/12/2008 - 18/12/2013

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.

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Expansion of a research laboratory 'Experimental Pathofysiology'. 01/02/2008 - 30/09/2013

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.

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The calcification paradox: investigation into the mechanisms underlying the association between metabolic bone disease and vascular calcification. 01/01/2008 - 31/12/2011

Abstract

Objectives: 1. Investigation of the association between vascular calcification and histomorphometric bone changes in osteoporotic rats with normal and impaired renal function by means of serial in vivo micro-CT scan and histomorphometric analysis of the bone. 2. Investigation of the role of the bone turnover rate and the effect of the bisphosphonate compound zoledronic acid on the development of uremia-related vascular calcification in different experimental models of renal osteodystrophy.

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The calcification paradox: experimental research into the association between bone pathology and vascular calcification with in vivo micro-CT imaging. 01/10/2007 - 30/09/2011

Abstract

This project aims at acquiring a broader understanding of the mechanisms underlying the association of disturbed bone metabolism and ectopic calcification of blood vessels with in vivo micro-CT analysis of bone changes as well as vascular calcifications in experimental rat models of osteoporosis and renal osteodystrophy.

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Investigation of renal and intestinal oxalate handling: new targets for preventive therapies in the field of renal calcifications. 01/10/2007 - 30/09/2011

Abstract

Aim: Investigate renal and intestinal oxalate handling as new targets for preventive therapies in the field of renal calcifications. Objectives: 1. Investigate the transepithelial transport of oxalate in human renal cells. 2. Investigate the effects of intestinal oxalate binding on oxalate excretion and incidence of renal calcifications.

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Cell biological and experimental study of the mechanisms and modulators underlying the protective effect of erythropoietin. 01/07/2007 - 31/12/2011

Abstract

Erythropoietin (EPO) has recently been shown to protect the kidney both functionally and morphologically against acute renal failure induced by ischemia/reperfusion injury, as seen for example after kidney transplantation. The mechanisms underlying this renoprotective effect are not known. This project aims to elucidate the mechanisms of the EPO-induced renoprotection both in vivo (ischemic rat model) and in vitro (human renal tubular cells culture), this in order to justify further clinical studies.

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In vivo and in vitro study into vascular calcifications with chronic renal insufficiency. 01/01/2007 - 31/12/2008

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The role of epithelial mesenchymal transition in the development of fibroses in the transplant kidney. 01/10/2006 - 30/09/2008

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Specification of the localisation of the epo receptor in human kidney cells using LCM and RT PCR. 01/06/2006 - 01/12/2006

Abstract

Eryhtropoietin (EPO) is an important hormone responsible for hematopoiesis. In addition to this EPO has various other functions. The functionality of EPO is also determined by its receptor (EPOR) that is mainly expressed in the kidney. A better insight in both the expression and localisation of the EPOR is mandatory to get a better insight in the function of EPO and its receptor. This will done by using the combination of laser capture microdissection and real-time PCR, a technique that is currently available in our lab.

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Preventive impact of EPO on the kidney after injury. 01/06/2006 - 01/12/2006

Abstract

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Causes and prevention of distal tubular crystal retention, an essential phase in the development of nephrocalcinosis and -lithiasis. 01/01/2006 - 31/12/2009

Abstract

In order to get a better insight in causes and prevention of nephrocalcinosis and -lithiasis, this project aims to answer the following questions: -is a non-differentiated distal tubular phenotype that is associated with damage/regeneration, the causal factor of crystal retention? -what is the role of osteopontin (OPN), CD44 and hyaluronic acid (HA) in the process of crystal retention? -can crystal retention be prevented by anti-inflammatory therapies?

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Role of the osteoblast in the development of renal osteodystrophy. A proteomics approach. 01/01/2005 - 31/12/2007

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Role of membrane organization and dynamics on cell behavior and response to external stimuli. 01/01/2005 - 31/12/2006

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In vivo and in vitro study into vascular calcifications in case of chronic renal insufficiency. 01/01/2005 - 31/12/2006

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In vitro and in vivo study into the mechanisms of vascular calcification in chronic renal failure. 01/10/2004 - 30/09/2007

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The role of epithelial-mesenchymal transition in the development of fibrosis in the transplanted kidney . 01/10/2004 - 30/09/2006

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Cellular and experimental research of causal factors in nephrolithiasis. 15/02/2004 - 30/09/2004

Abstract

Retention of crystals in renal tubuli leads to the formation of kidney stones. Multiple factors have been correlated with this initial phase of nephrolithiasis: renal injury/-regeneration, upregulation of osteopontin (OPN) and hyaluronan (HA) - known crystal binding molecules - and redistribution of their common receptor CD44. In this study we will try to elucidate the role of renal injury, OPN and HA in crystal retention by using animal models of nephrolithiasis on one hand and OPN knock-out mice, where both in vivo and in vitro experiments will be performed, on the other.

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ATOM : Advanced Tomography. 01/01/2004 - 31/12/2007

Abstract

The main goal of the project is the development/improvement of advanced forms of tomography and its application in practice. On the one hand attention will be paid to the development of tomography at the nanoscopic level by means of EFTEM while on the other hand element-specific X-ray fluorescence tomography with micrometer resolution will be optimised and quantitatively calibrated. An important area of application is the quantitative three-dimensional measurement of various phases in (human and animal) bone.

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Comparative experimental and cell biological study on the mechanisms underlying the effects of some trace metals (Sr, La, Al) on the bone metabolism/mineralisation in chronic renal failure. 01/01/2003 - 31/12/2006

Abstract

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Experimental and cell biological assessment of the effects of lanthanum and strontium on osteoblast function and process of bone mineralization 01/10/2002 - 30/09/2006

Abstract

Following previous findings in the Laboratory of Nephrology-Hypertension demonstrating both strontium and lanthanum to induce bone lesions in an experimental rat model with chronic renal failure, which histologically are expressed as osteomalacia, it will in the present research project be investigated wether the mineralization defect resulting from exposure to these elements, develops via an identical pathway. Therefore it will be assessed whether the disturbed mineralization is due to a pure physicochemical, extracellular process or on the other hand occurs via a direct effect on the osteoblast. Also will the interference of both elements with the secretion/synthesis of a series of relevant bone matrix proteins be investigated. To find an answer to these questions in vitro (primary osteoblast cultures) as well as in vivo (rat model with chronic renal failure) set-ups will be applied.

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Role of macrophages and T-cells in acute renal ischemia/reperfusion injury and chronic renal failure. 01/01/2002 - 31/12/2005

Abstract

ARF still affects 5% of all hospitalized patients, a disease for which no specific therapy is available. ARF still carries a very high mortality rate of more than 50%. The mechanisms underlying this syndrome are still poorly understood. An ischemic insult of the kidney results in ARF, going along with tubular necro-sis of the S3-segment of the proximal tubular cells. This leukocyte infiltrate exists of mononuclear cells, i.e. monocytes/macrophages and helper-T cell. Accumu-lation of polymorphonuclear cells is absent after IRI. Evidence that these inflammatory cells play a role in renal IRI came from studies showing that antibodies against adhesion molecules such as ICAM-1 and an-tibodies against T-cell/antigen-presenting cell 'costimulatory pathway B7-CD28' (CTLA-4 Ig/anti-B7) resulted in a clear protection (functional and morphological). Stimulation of B7-1 results in a Th-1 cytokine profile whereas B7-2 results in a Th-2 profile. Which kind of acti-vated inflammatory cells, trapped in the vasa recta of the ischemic kidney, expressing CD28 needs further investigation. The ever-increasing proportion of marginal donors for kidney transplantation and the problems these en-tail got our research group interested in studying chronic renal failure and the effect of superposition of an acute ischemic insult on chronic renal failure. In remnant kidney model (in the rat), 5/6 nephrectomy in-duces a moderate chronic renal failure, accompanied histologically by tubulointerstitial injury and a leu-kocyte infiltrate rich in macrophages. We demonstrated that these chronic renal failure animals were par-tially protected, both functionally and morphologically, against an acute ischemic insult to the kidney. It is as yet unknown which factors are responsible for this absence of increase in leukocyte infiltration in chronic renal failure animals after acute I/R injury. We showed a dramatic upregulation of this protein after acute IRI, with OPN being expressed in perinuclear, vesicular structures in proximal tubules and at the apical cell side in distal tubules. We have recently confirmed this role in OPN knockout mice: after I/R these animals showed significantly less macrophage infiltration in comparison with nor-mal mice.

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Experimentar and cel\ biological investigation of the mechanisms underlying the development of a mineralisation defect secondary to an increased exposure to trace metals in chronic renal failure. 01/01/2001 - 31/12/2004

Abstract

In patients with chronic renal failure the interaction between the reduced renal function and increased exposure to a number of trace elements such as lanthanum, strontium and aluminum may result in the development of a mineralisation defect. In the frame of the present BOF project using both in vivo (chronic renal failure rat model) and in vitro (mineralizing osteoblast cultures) set ups we are aiming to assess whether the effe cts of the above mentioned trace elements (i) result from pure physicochemical, extracellul ar processes (ii) are mediated by the interference of these elements with a number of functional osteoblastic parameters (iii) are influenced by the degree of bone turnover (adynamic bone vs. hyperparathyroidism).

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The role of Silicon in Bone Metabolism. 01/06/2000 - 31/05/2003

Abstract

Silicon is considered an essential element which might exert a beneficial effect on bone metabolism. In view of this it will in the present study be investigated to which extent the administration of silicon may be used in the treatment of osteoporosis Therefore a certain silicon compound (OSA) will be administered to ovariectomized rats, used as models for bone loss whereafter the bone remodeling (bone formation/bone resorption) will be compared to a control population.

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    Multiparametric flow cytometric isolation and study of relevant cell populations in hematology, immunology, nephrology and oncology. 01/01/2000 - 31/12/2000

    Abstract

    The evaluation of the function or dysfunction of specific cells within a given organ requires in many cases the preceding viable isolation of these cells from a -sometimes- abundant amount of unwanted accessory cells. For this a number of cell separation techniques are available based on physical properties such as differences in cell density, cell adhesion, immunoaffinity etc' However, the flow cytometric cell sorting technique (based on electrostatic droplet formation) is the only separation technique that permits to separate different cell populations (up to 4) while simultaneously evaluating quite a number of properties such as size, internal complexity, DNA-content, presence or absence of up to 4 or 5 surface or cytoplasmic antigens. Since different cell populations may differ in subtle ways from others, this multiparametric flow cytometric sorting approach is in many cases a prerequisite to isolate the cells of interest: the primitive hematopoietic cell can only be defined by multiparametric labelling, kidney cell subpopulations, malignant versus normal cells, cell populations that are different in terms of cell cycle rate etc' It is clear that the availability of a cell sorter is a prerequisite for the four applying groups to study their respective cell(s) of interest. From 1990 onwards three of the four groups have built up expertise in the field, by joining forces and collaborating in the purchase of a FACStarPlus cell sorter. The output of numerous articles and several PhD theses may serve as proof of the good management of this interdisciplinary sorting facility. After 8 years of continuous heavy use, and in order to guarantee continuity in their research, the three initial groups, together with a fourth group (Tropical Medicine, Immunology) that meanwhile established close collaboration, now consider the purchase of a new generation cell sorter to be a priority. The growing number of users and applications have made the workload on the old instrument critically high. More elaborate simultaneous labelling and multiple and faster sorts are necessary to efficiently use the 'sometimes- scarce available starting material. This can only be accomplished by the new generation machines that guarantee much higher sort rates (up to > 30,000 cells/second, compared to 3000 cells/second on the old equipment) . Aerosol control systems implemented in the new machines offers prospects for work with potentially infectuous material (tropical medicine) The laser configuration of the old system is inadequate and the storage capacity and compatibility of the old computer system do not satisfy anymore the actual needs of a multi-user multidisciplinary facility. In what follows we will highlight the objectives and activities of the different research groups. It should be clear that no effort is made to link the respective topics: indeed the research topics described in this funding application are heterogeneous. Apart from some obvious common interests, the major link of these groups is the awareness that they all need cell sorting facilities to reach their goals.

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      Experimental investigation on the effects of strontium and lanthanum on bone remodeling in a chronic renal failure rat model. 01/10/1999 - 31/12/2000

      Abstract

      This research aims at : (1) to investigate possible effects of lanthanum on bone parameters in relation to well-known chemical data of bone turnover (2) to study the role of strontium on bone mineralisation.

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        Physiopathological role of strontium in the development of osteomalacia in renal failure, its interference with osteopontin and vitamin D, during the bone mineralisation process. 01/01/1998 - 31/12/2001

        Abstract

        In order to get a better insight in the mechanisms underlying the development of strontium-induced osteomalacia it will be looked for whether strontium either plays a direct (e.g. disturbance of the crystal cattice), or indirect role (e.g. interference with alkaline phosphatase and osteopontin at the level of the osteoblast, interference with 1-alfa hydroxylase at the level of the tubular cell).

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          The role of exposure to silica in ANCA-associated glomerulonephritides. 01/01/1995 - 31/12/1997

          Abstract

          This study, aiming to study the association between occupational exposure to silicon-containing compounds and the development of ANCA-positive glomerulonephritis, consists in 4 interdependent parts. A case-control study will determine the risk ratio of nephrotoxicity after silica- exposure. In a toxicological part, broncho-alveolar lavage fluid will be investigated. During a chemical analysis, the identificatian/specification of the silicon particle will be studied. A experimental part aims to obtain more insight in the pathophysiological mechanism using a ratmodel with inhalation of silica particles.

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            Hypoparathyroidism - adynamic bone disease in the end-stage renal failure patient : study of causal factors. 01/01/1994 - 31/12/1994

            Abstract

            It will be investigated whether the uptake of aluminium by the parathryoidgland happens via transferrin mediated endocytosis and to which extent this uptake mechanism interferes with the PTH synthesis/secretion and growth of the parathyroid cell. Moreover, besides aluminium it will be looked for whether sillicon contributes to the high prevalence of adynamic bone in the dialysis population also.

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              speciation and protein binding of trace metals by the AAS-HPLC hybride technique 01/01/1992 - 31/12/1992

              Abstract

              To improve the insights in the toxicity of trace elements, an accurate and precise method is developed using the combination AAS/HPLC (AAS = atomic absorption spectrometry) allowing the investigation of their protein binding and speciation in biological fluids

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