Research Pieter-Jan Guns

Abstract

Recently, we discovered upregulation of SERPINA3, or alpha-1-antichymotrypsin, in both mice and patients with doxorubicin-induced cardiovascular toxicity. Also other clinical studies have reported SERPINA3 to be associated with adverse cardiovascular outcome in recent years. However, despite its prognostic potential for cardiovascular disease (CVD), the role of SERPINA3 in cardiovascular pathology remains poorly understood, and it is unknown whether SERPINA3 is part of a coping or disease mechanism. As such, the current proposal aims to shed light on the role of SERPINA3 in cardiovascular pathology by pursuing a translational approach. In vivo studies combining in-house well-established murine models of cardiovascular toxicity and heart failure (HF) with a SERPINA3 knock-out mouse strain will provide unique insight into the (patho)physiological role of SERPINA3. Moreover, single-cell RNA sequencing on cardiac and aortic tissue, complemented by in vitro work, will identify the molecular pathways involving SERPINA3 and its cellular source. Finally, the preclinical findings will be validated in HF patients by assessing the association of serum SERPINA3 with functional and molecular data of an existing cohort of HF patients. Ultimately, this project will determine whether elevated SERPINA3 levels pose cardiovascular risk for patients and further validate its prognostic value as well as elucidate the functional and molecular role of SERPINA3 in cardiovascular (patho)physiology.

Researcher(s)

• Promoter: Guns Pieter-Jan
• Co-promoter: Martinet Wim
• Fellow: Bosman Matthias

Research team(s)

• Physiopharmacology (PHYSPHAR)

Project type(s)

• Research Project

Abstract

Recently, we discovered upregulation of a certain protein (SERPINA3) in a mouse model of chemotherapy-related cardiac dysfunction (CTRCD). This observation was confirmed by higher SERPINA3 plasma levels in patients with CTRCD. Growing evidence points to SERPINA3 as prognostic marker in cardiovascular disease, yet its role in cardiovascular pathology is poorly understood. The current proposal will shed light on the role of SERPINA3 in CTRCD, as well as its possible use as predictive marker. A bench to bedside approach will be implemented taking advantage of an established experimental mouse model of CTRCD induced by doxorubicin, combined with a prospective clinical trial in anthracycline-treated lymphoma patients. First, SERPINA3 knockout and wild type mice will be subjected to CTRCD to investigate the role of SERPINA3 in cardiac and vascular dysfunction. More specifically, the role of SERPINA3 on inflammatory pathways, as well as on ferroptosis will be evaluated. The in vivo study will be complemented with in vitro experiments with primary endothelial cells (EC), cardiomyocytes and vascular smooth muscle cells. A second part involves a translational in vivo study aimed to evaluate the effect of cardioprotective (heart failure, HF) drugs (i.e., an ACE-inhibitor+betablocker and an SGLT2-inhibitor) in the CTRCD mouse model with specific focus on SERPINA3 and EC-function. Finally, a third part involves a prospective, multicentric, observational study in lymphoma patients treated with anthracycline-based chemotherapy to investigate plasma SERPINA3 and retinal EC-function during CTRCD and its treatment with HF drugs. Ultimately, this project will contribute to the validation of SERPINA3 as predictive marker and will provide proof of concept of SERPINA3 as therapeutic strategy.

Researcher(s)

• Promoter: Guns Pieter-Jan
• Co-promoter: Franssen Constantijn

Research team(s)

• Physiopharmacology (PHYSPHAR)

Project type(s)

• Research Project

Abstract

The attrition rate of novel drug candidates due to cardiotoxic adverse events remains a big challenge in the preclinical and clinical drug development. As such, it is pivotal for the pharmaceutical industry to identify these liabilities at early stages by applying sensitive and translatable assaysto predict potential harmful effects to the human cardiovascular system. The current project aims to develop and optimize an assay in human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) that combines impedance and multi-electrode array (MEA) measurements with cardiotoxicity biomarkers, in particular dysregulated microRNAs (miRNAs). To achieve this goal, commercially available hiPSC-CM were treated with a large set of drugs at clinically relevant concentrations, and drug responses were monitored for 72h on XCELLigence Real Time Cell Analysis (RTCA) Cardio ExtraCellular Recording (ECR) instrument measuring impedance and electrical changes. RT-qPCR on RNA extracted from the cell pellets was employed to study the upregulation of previously identified miRNAs candidates (Gryshkova et al. Arch of Toxicology, 2022). Several miRNAs were found to be upregulated in hiPSC-CM, especially in response to anthracycline drugs. hsa-miR-187-3p, hsa-miR-182-5p, hsa-miR-365a-5p, and hsa-miR-133b were upregulated with the highest fold changes in response to several treatments. In the past decade, several studies have confirmed the expression of dysregulated miRNAs in the blood/serum of patients with various diseases, spacing from oncological disorders to cardiovascular liabilities. Therefore, the investigation of miRNAs released in the supernatant of hiPSC-CM culture could confirm their utility as potential novel biomarkers of cardiotoxicity in the clinic. To assess the translatability of the already generated data and the effect of existing genetic cardiac liabilities on cardiotoxic drug exposure, the assays will be applied to in-house created hiPSC-CMs from patients carrying TTN and SCN5A mutations, causing cardiomyopathy and the cardiac arrhythmia Brugada syndrome respectively, and healthy control individuals (isogenic and unrelated controls). Impedance and electrophysiology will be measured on these cell lines by RTCA CardioECR and alteration in expression level of the selected miRNAs will be analyzed both in the cell pellet and the supernatant. In addition, expression level of the selected miRNAs will be analyzed in blood samples collected from the same individuals as well as a selection of cardio-oncology patients.

Researcher(s)

• Promoter: Alaerts Maaike
• Co-promoter: Guns Pieter-Jan

Research team(s)

• Medical Genetics (MEDGEN)

Project type(s)

• Research Project

Abstract

Doxorubicin (DOX) is a widely used and highly effective chemotherapeutic agent with severe side effects, affecting the quality of life of cancer patients and survivors. DOX-induced skeletal muscle toxicity, especially muscle wasting and dysfunction, is of particular concern as it increases morbidity and mortality rates. In the current proposal, we aim to investigate the role of myokines and miRNAs within the mechanisms of DOX-induced skeletal muscle wasting through an in vitro (C2C12 cell line) and in vivo (mice) model. Identification of these myokines and miRNAs, that are expressed and exert their action in skeletal muscle, offer a novel theoretical basis to unravel the underlying cellular and molecular mechanisms and provide novel insights in the diagnosis and treatment of skeletal muscle wasting following DOX-treatment. We hypothesize that myokines and miRNAs play a crucial role in the pathogenesis of DOX-induced skeletal muscle wasting. In addition, we will study the potential cellular and molecular counteracting effects of muscle contraction on muscle wasting by 1) electrical pulse stimulation on DOX-treated C2C12 cells and 2) single exercise bouts in mice immediately before each DOX-cycle. We hypothesize that exercise is a feasible strategy in clinical practice to prevent DOX-induced muscle wasting. Finally, to improve clinical translatability we will also study the therapeutic use of single exercise bouts in a murine cancer cachexia model treated with DOX.

Researcher(s)

• Promoter: van Breda Eric
• Co-promoter: Guns Pieter-Jan
• Co-promoter: Van Craenenbroeck Emeline
• Fellow: Van Asbroeck Birgit

Research team(s)

• Movement Antwerp (MOVANT)

Project type(s)

• Research Project

Abstract

Despite exercise being our oldest and most efficacious medicine, animal and human data suggest that excessive exercise may contribute to pathological cardiac remodelling in some, resulting in increased susceptibility for atrial and ventricular arrhythmias and sudden cardiac death. One hallmark of this pathological remodelling is the development of myocardial fibrosis (MF). In two specific types of MF in athletes (i.e. insertion point MF and right ventricular fibrosis in the context of arrhythmogenic cardiomyopathy), exercise contributes as a causal factor. We hypothesise that exercise also contributes to the development of MF in the left ventricle after (silent) myocarditis, which could explain its higher incidence in athletes. We will verify this hypothesis in a murine coxsackie B virus-induced myocarditis and exercise model. MF will be evaluated by standard histology, as well as by whole mount 3D microscopic imaging. Further, innovative serial multiplex immunohistochemistry (IHC) will be used for detailed cellular and molecular phenotyping, providing unrivalled insights into (patho)physiological remodelling during myocaditis. In addition, the modulating effect of NSAIDs will be evaluated. In parallel, clinical studies are conducted to gain insight into the aetiology and evolution of MF in athletes. Ultimately, our results will contribute to the development of guidelines on safe sport participation and NSAIDs use in the setting of viral syndromes.

Researcher(s)

• Promoter: Heidbuchel Hein
• Co-promoter: Guns Pieter-Jan

Research team(s)

• Cardiovascular diseases (CARDIOVASC)

Project type(s)

• Research Project

Abstract

The proposed Scientific Research Network aims to stimulate the investigation of save/efficient treatments for arterial media calcifications in Flanders. The specific aims of are to further investigate: (1) the role of extracellular nucleotides in arterial media calcification prevention/treatment, (2) the bone-vascular axis and (3) beneficial impact of arterial media calcification treatment on arterial stiffness.

Researcher(s)

• Promoter: Verhulst Anja
• Co-promoter: Guns Pieter-Jan

Research team(s)

• Cell death signaling (CDS)

Project type(s)

• Research Project

Abstract

Safety pharmacology is an essential part of drug development and aims to identify and investigate adverse events of a drug before entering trials which involve human subjects. In particular, negative effects on the cardiovascular system have stopped many drug development programs. Safety pharmacology has successfully implemented a screening strategy to detect undesirable cardiovascular effects, but there is still room for improvement. Regulations recommend conducting an assessments of drug-induced changes on the heart rate and blood pressure in awake animals. Evaluation of cardiovascular function in animal experimentation leads to acceptable translation to humans, yet it provides limited mechanistic insight and risk assessment may be challenging. The current research aims to evaluate arterial stiffness as a possible marker of drug-induced cardiovascular effects. Arterial stiffness increases with age and is a blood pressure-independent prognostic factor for cardiovascular disease. However, it has not been widely considered in safety pharmacology. Interestingly, arterial stiffness is a single parameter and integrates information on both structural (matrix) stiffness as well as active regulation of vascular tone. Moreover, vascular tone reflects the balance between the action of contractile vascular smooth muscle cells and vasodilation-promoting endothelial cells. In the current project we will evaluate drug-induced changes in arterial stiffness both in vivo by measuring pulse wave velocity (PWV) by ultrasound imaging and ex vivo in a proprietary organ bath set-up. More specifically, the research will focus on the investigation of a number of anti-cancer drugs (doxorubicin, VEGF-inhibitors and proteasome inhibitors) and their respective effects on endothelial cell function, matrix stiffness and arterial stiffness since growing evidence suggests that cardiotoxic effects of anti-cancer drugs extend beyond the heart and may predispose to (or facilitate) cardiovascular disease.

Researcher(s)

• Promoter: Guns Pieter-Jan
• Fellow: Wesley Callan

Research team(s)

• Physiopharmacology (PHYSPHAR)

Project type(s)

• Research Project

Abstract

Advancements in cancer therapy have led to a growing population of cancer survivors. Concomitant with the improved prognosis, there is growing concern about the possible adverse effects of cancer treatments. Especially cardiovascular toxicity is a growing clinical concern and today's cancer patients may become tomorrow's heart failure patients. Currently, there are no effective diagnostic strategies or treatments to prevent patients from developing cardiovascular toxicity, leading to a shift in the health problem from oncology to cardiology. The central hypothesis of the current project is that endothelial cell dysfunction, driven by inflammation and oxidative stress, is the earliest stage of cardiovascular toxicity induced by cancer treatments, and that early diagnosis will allow for better cardioprotective treatments and improved cancer therapy outcomes. This translational project will experimentally investigate endothelial cell function and associated markers in mice treated with the chemotherapeutic doxorubicin, VEGF inhibitors, and immune checkpoint inhibitors. The key focus of the research will be on the evaluation of a potential novel biomarker, circulating serin protease inhibitor Serpina3n, which has been found to be implemented in cardiovascular disease, including heart failure. Serpina3 will be validated as potential diagnostic marker in the mice models, as well as in breast cancer patients who undergo serial cardiovascular studies before, during, and after cancer treatment. The ultimate goal is to better understand the role of Serpina3 in drug-induced cardiotoxicity and potentially develop new strategies to prevent or mitigate cardiovascular toxicity in cancer patients.

Researcher(s)

• Promoter: Guns Pieter-Jan

Research team(s)

• Physiopharmacology (PHYSPHAR)

Project type(s)

• Research Project

Abstract

In the last century, the enormous improvements in life expectancy have led to a global population that has grown considerably older. The number of people over 65 is expected to increase from an estimated 524 million in 2010 to nearly 1.5 billion in 2050 (source WHO). Therefore, age-related diseases such as cardiovascular disease (CVD), diabetes, kidney disease and neurological disorders have a significant impact on our quality of life and represent a huge social and economic burden. Vascular ageing is characterized by structural and functional changes in the wall of large arteries, leading to arterial stiffness, which is an independent predictor of cardiovascular complications. Moreover, there is increasing evidence that it is a key driving force for multiple age-related cardiac, renal and cerebral pathologies. This challenge aims to better understand the pathophysiological mechanisms causing vascular ageing and arterial stiffness in order to prevent or delay this process and improve quality of life. The focus will be on the role of autophagy in vascular ageing, which is a homeostatic process that supports cell survival under stressful conditions. The autophagic process becomes impaired as we age, contributing to the development of age-related diseases. However, many questions about why autophagy declines and how it can be therapeutically targeted, still remain unanswered.

Researcher(s)

• Promoter: Roth Lynn
• Co-promoter: De Meyer Guido
• Co-promoter: Guns Pieter-Jan
• Co-promoter: Martinet Wim
• Fellow: Neutel Cédric

Research team(s)

• Physiopharmacology (PHYSPHAR)

Project type(s)

• Research Project

Abstract

Despite physical exercise being our oldest and most efficacious medicine, animal and human data suggest that excessive exercise may contribute to pathological cardiac remodelling, resulting in increased susceptibility for atrial and ventricular arrhythmias and sudden cardiac death. One hallmark of this pathological remodelling is the development of myocardial fibrosis (MF). In two types of MF in athletes, insertion point MF and right ventricular fibrosis in the context of arrhythmogenic cardiomyopathy, exercise contributes as a causal factor. We hypothesise that exercise also contributes to the development of MF in the left ventricle after (silent) myocarditis, which could explain its higher incidence in athletes. We will verify this hypothesis in a murine coxsackie B virus-induced myocarditis and exercise model. Standard histological, RT-qPCR and immunohistochemical analysis, including the use of tissue clearing, will provide further insights into (patho)physiological remodelling and molecular pathways. In addition, the modulating effect of NSAID and several exercise variables (intensity and timing relative to the onset of myocarditis) on the aforementioned interaction between myocarditis and physical exercise will be evaluated. Simultaneously, a multicentre registry (including serial cardiac magnetic resonance imaging and viral PCR on endomyocardial biopsies) is conducted to gain insight into the aetiology of MF in athletes.

Researcher(s)

• Promoter: Heidbuchel Hein
• Co-promoter: Guns Pieter-Jan
• Fellow: Favere Kasper

Research team(s)

• Cardiovascular diseases (CARDIOVASC)

Project type(s)

• Research Project

Abstract

Cancer survival has increased significantly over the last decades because of improved screening and the development of novel therapies. The downside of this positive evolution is that cancer treatment-related adverse events affecting the quality of life of cancer survivors has become an emerging concern. Physical long-term side effects of anthracycline chemotherapy, such as doxorubicin (DOX) and Cisplatin (CIS), include cardiovascular complications (heart failure), peripheral fatigue and muscle mass loss (wasting). While the cardiovascular toxicity of DOX has been extensively studied, this project aim to investigate the effects of DOX and/or CIS on skeletal muscle structure and (mitochondrial) metabolism. Additionally, we will evaluate the possible beneficial effect of physical exercise as a strategy to protect against DOX and CIS induced myotoxicity. This project aims to lay the foundation of a novel joint research line of the research groups of Movant, Cardiovascular Disease and Physiopharmacology to exploit scientific and operational synergies.

Researcher(s)

• Promoter: van Breda Eric
• Co-promoter: Guns Pieter-Jan
• Co-promoter: Van Craenenbroeck Emeline
• Fellow: Van Asbroeck Birgit

Research team(s)

• Movement Antwerp (MOVANT)

Project type(s)

• Research Project

Abstract

New drug candidates often have off-target effects resulting in adverse events, thus representing a major limitation for drug R&D. Safety Pharmacology (SP) aims to detect, understand and reduce undesirable pharmacodynamic effects early-on. Especially, cardiovascular (CV) toxicity is problematic, as it is the most prevalent reason for failure during preclinical development. Moreover, CV toxicity remains a key reason for drug attrition during clinical development and beyond. This indicates current SP screens fail to detect a number of (late-onset) functional or structural CV toxicities. Additionally, SP uses a significant number of laboratory animals, thereby creating opportunities for a better implementation of the 3Rs. The vision of INSPIRE is to advance and "inspire" SP by exploring new technological capabilities (WP1), addressing emerging CV concerns (WP2) and delivering new validated solutions for CV safety screening (WP3). To this end, INSPIRE unites expertise from academic teams, technology-providers, pharmaceutical companies, regulators and hospitals to create a European training platform for 15 Early Stage Researchers (ESRs). Key innovative aspects of INSPIRE include: i) in vitro humanized cardiomyocytes assays, ii) unparalleled in vivo hardware/software solutions, iii) in silico predictions of haemodynamics, iv) mass spectroscopy imaging of drug exposure, v) exploration of mechanisms of late-onset CV toxicity, as observed in cardio-oncology, and vi) early integration of feedback from industry and regulators. Overall, INSPIRE constitutes a multidisciplinary and intersectoral training programme (WP4) with a balanced combination of hands-on research training, intersectoral secondments, local courses and network-wide events on scientific and transferable skills, enabling future R&I collaborations. Hence, INSPIRE will equip the future generation of SP scientists with a wide range of scientific knowledge and the ability to adapt to a dynamic ever-changing industry.

Researcher(s)

• Promoter: Guns Pieter-Jan
• Co-promoter: De Meyer Guido
• Co-promoter: Heidbuchel Hein
• Co-promoter: Martinet Wim
• Co-promoter: Segers Vincent
• Co-promoter: Van Craenenbroeck Emeline

Research team(s)

• Physiopharmacology (PHYSPHAR)

Project type(s)

• Research Project

Abstract

Cardiovascular calcification significantly contributes to cardiovascular disease, which is the leading cause of mortality and a major cause of morbidity in Europe. Cardiovascular calcification occurs in both rare monogenic (e.g. pseudoxanthoma elasticum) and in common acquired diseases (e.g. atherosclerosis and chronic kidney disease). Importantly, cardiovascular calcification is an active but incompletely understood process regulated by a variety of (epi)genetic and environmental factors, acting both systemically and locally. Despite its major clinical impact, no specific therapeutic strategies targeting cardiovascular calcification are applied in current clinical practice. In 2019, the Physiopharmacology and Pathophysiology research groups of the University of Antwerp were both part of the "eRaDiCal" consortium (H2020-MSCA-ITN call) aimed to investigate risk factors and underlying mechanisms across rare and common ectopic calcification disorders for the development of adequate diagnostic, preventive and therapeutic solutions to target cardiovascular calcification. eRaDiCal received an excellent reviewer score (94.8%, reserve list), but was not funded. As part of its strategic research plan, the University of Antwerp provides funding for excellent H2020 proposals to facilitate and encourage a successful resubmission. The teams of Physiopharmacology and Pathophysiology will use the budget to substantiate the evidence base on the role of autophagy in arterial calcification and stiffness. The intention is to recruit a (part-time) postdoc and/or PhD student to obtain preliminary data during the next year.

Researcher(s)

• Promoter: Guns Pieter-Jan
• Co-promoter: Verhulst Anja

Research team(s)

• Physiopharmacology (PHYSPHAR)

Project type(s)

• Research Project

Abstract

Anthracyclines (such as doxorubicin, DOX) are among the most effective chemotherapeutics and are widely used in modern cancer treatment despite the advent of targeted therapies. However, dosedependent cardiotoxicity limits the clinical use of DOX. It is well documented that DOX may provoke cardiotoxicity leading to left ventricular dysfunction and eventually congestive heart failure. Recent studies have reported that anthracyclines also interfere with arterial stiffness, an overall measure of vascular health. However, it is unclear whether vascular toxicity occurs through the same mechanisms and pathways as the cardiac toxicity. Moreover, the clinical implications of increased arterial stiffness due to DOX, either as contributing mechanism to cardiotoxicity or as early marker of accelerated cardiovascular aging in (childhood) cancer survivors is incompletely understood. The current research proposal aims to shed light on the mechanisms and clinical relevance of DOX-induced vascular toxicity by pursuing a translational experimental research approach.

Researcher(s)

• Promoter: Guns Pieter-Jan
• Fellow: Bosman Matthias

Research team(s)

• Physiopharmacology (PHYSPHAR)

Project type(s)

• Research Project

Abstract

Autophagy is a normal physiological process that maintains intracellular homeostasis by degrading unnecessary or dysfunctional cellular components in lysosomes. This way, autophagy supports cell survival in unfavourable conditions and represents a reparative and life-sustaining process. Impaired autophagy is increasingly recognized as a hallmark of aging and of multiple human pathological conditions, including cardiovascular disease. Moreover, impaired autophagy has been linked with increased arterial stiffness, an independent risk marker of cardiovascular disease. Therefore, inducing autophagy could be a game-changer in the treatment of cardiovascular disease. However the potential of autophagy inducing drugs has not been realized yet due to the absence of potent and selective tool compounds. The current proposal will start from a number of hits identified in a high-throughput screening and will further validate these lead candidates through a series of in vitro and in vivo studies focussing on vascular biology. Using geneticallyengineered mice with cell-type specific autophagy defect, the selectivity of the final lead compound will be demonstrated. Moreover, we aim to establish preclincal proof of concept of autophagy induction as therapeutic strategy for cardiovascular ageing and the development of atherosclerosis.

Researcher(s)

• Promoter: Guns Pieter-Jan
• Co-promoter: Martinet Wim
• Fellow: Neutel Cédric

Research team(s)

• Physiopharmacology (PHYSPHAR)

Project type(s)

• Research Project

Abstract

Despite physical exercise being our oldest and most efficacious medicine, animal and human data suggest that excessive exercise may contribute to pathological cardiac remodelling, resulting in increased susceptibility for atrial and ventricular arrhythmias and sudden cardiac death. One hallmark of this pathological remodelling is the development of myocardial fibrosis (MF). In two types of MF in athletes, insertion point MF and right ventricular fibrosis in the context of arrhythmogenic cardiomyopathy, exercise contributes as a causal factor. We hypothesise that exercise also contributes to the development of MF in the left ventricle after (silent) myocarditis, which could explain its higher incidence in athletes. We will verify this hypothesis in a murine coxsackie B virus-induced myocarditis and exercise model. Standard histological, RT-qPCR and immunohistochemical analysis, including the use of tissue clearing, will provide further insights into (patho)physiological remodelling and molecular pathways. In addition, the modulating effect of NSAID and several exercise variables (intensity and timing relative to the onset of myocarditis) on the aforementioned interaction between myocarditis and physical exercise will be evaluated. Simultaneously, a multicentre registry (including serial cardiac magnetic resonance imaging and viral PCR on endomyocardial biopsies) is conducted to gain insight into the aetiology of MF in athletes.

Researcher(s)

• Promoter: Heidbuchel Hein
• Co-promoter: Guns Pieter-Jan
• Fellow: Favere Kasper

Research team(s)

• Cardiovascular diseases (CARDIOVASC)

Project type(s)

• Research Project

Abstract

Anthracyclines (such as doxorubicin, DOX) are among the most effective chemotherapeutics and are widely used in modern cancer treatment despite the advent of targeted therapies. However, dose-dependent cardiotoxicity limits the clinical use of DOX. It is well documented that DOX may provoke cardiotoxicity leading to left ventricular dysfunction and eventually congestive heart failure. Recent studies have reported that anthracyclines also interfere with arterial stiffness, an overall measure of vascular health. However, it is unclear whether vascular toxicity occurs through the same mechanisms and pathways as the cardiac toxicity. The current research proposal aims to shed light on the mechanisms and clinical relevance of DOX-induced vascular toxicity by pursuing a translational experimental research approach.

Researcher(s)

• Promoter: Guns Pieter-Jan
• Fellow: Favere Kasper

Research team(s)

• Physiopharmacology (PHYSPHAR)

Project type(s)

• Research Project

Abstract

The increasing effectiveness of multimodality cancer treatment, including medical imaging for diagnosis followed by surgery, chemotherapy, and radiation therapy, has significantly improved the outcome for many cancer patients. However, this also implies that long-term side effects inducted by therapy have become an important issue. External beam radiation therapy (RT) plays an important role in the management of patients with cancer. For instance, in breast cancer RT also covers part of the heart and major blood vessels. Moreover, low to mediate radiation doses associated with RT have been correlated with an increased cardiovascular morbidity and mortality. In the framework of the recently launched European Horizon2020 project MEDIRAD, we aim to explore: i) DNA methylation patterns as relevant biomarkers of radiation-induced cardiovascular damage. To this end, we will first identify DNA methylation patterns in blood samples of animal models exposed to ionizing radiation. Next, the developed biomarker panel will be cross-validated in blood samples from breast cancer RT-therapy patients (Early-Heart cohort). In parallel, we will study the effect of low-dose radiation on vascular reactivity and associated vascular stiffness in animal models. ii) microRNAs (miRNAs) and long (lncRNAs) non-coding RNAs as biomarkers for diagnosis and prognosis of cancer (e.g. after CT radiation exposure). A number of miRNA and lncRNA have been identified recently as important epigenetic regulators with critical roles in cancer invasion (such as miR-128, miR-129-2, miR-215, HOTAIR, MEG3). These epigenetic regulators affect gene expression without changing the DNA sequence. We will develop an RT-PCR assay made of up to 20 candidate miRNA and/or lncRNA identified based on data-mining of web-accessible databases. Next, blood and saliva samples from patients with brain tumours, leukaemia and healthy controls (all from the EpiCT study) will be analysed to investigate whether miRNA/lncRNAs are potential markers of radiosensitivity and may predict the development of specific malignancies. Taken together, this research project aims to identify a set of predictive biomarkers for a more accurate risk estimation for early and late radiation-induced cardiovascular and neoplastic events, as well as to provide potential targets for countermeasures. As such, we strive for a better life quality for ionizing radiation exposed people.

Researcher(s)

• Promoter: Guns Pieter-Jan
• Fellow: Sallam Magy

Research team(s)

• Physiopharmacology (PHYSPHAR)

Project type(s)

• Research Project

Abstract

Autophagy is a normal physiological process that maintains intracellular homeostasis by degrading unnecessary or dysfunctional cellular components in lysosomes. This way, autophagy supports cell survival in unfavourable conditions and represents a reparative and life-sustaining process. Impaired autophagy is increasingly recognized as a hallmark of aging and of multiple human pathological conditions, including cardiovascular disease. Inducing autophagy could be a game-changer in the treatment of cardiovascular disease, but the potential of autophagy inducing drugs has not been realized yet due to the absence of potent and selective tool compounds. The current proposal will start from a number of hits identified in a high-throughput screening and will further validate these lead candidates through a series of in vitro and in vivo studies focussing on vascular biology.

Researcher(s)

• Promoter: Guns Pieter-Jan
• Fellow: Neutel Cédric

Research team(s)

• Physiopharmacology (PHYSPHAR)

Project type(s)

• Research Project

Abstract

Magnetic resonance imaging (MRI) is one of the most useful and rapidly growing neuroimaging tools. Unfortunately, signal intensities in conventional MRI images are expressed in relative units that depend on scanner hardware and acquisition protocols. While this does not hinder visual inspection of anatomy, it hampers quantitative comparison of tissue properties within a scan, between successive scans, and between subjects. In contrast, advanced quantitative MRI (Q-MRI) methods like MR relaxometry or diffusion MRI do enable absolute quantification of biophysical tissue characteristics. Evidence is growing that Q-MRI techniques detect subtle microscopic damage, enabling more accurate and early diagnosis of neurodegenerative diseases. However, due to the long scan time required for Q-MRI, causing discomfort for patients and limiting the throughput, Q-MRI methods have not entered clinical practice yet. B-Q MINDED aims to overcome the current barriers by developing widely-applicable post-processing breakthroughs for accelerating Q-MRI. The originality of B-Q MINDED lies in its ambition to replace the conventional rigid multi-step processing pipeline with an integrated single-step parameter estimation framework. This approach will unlock a wealth of options for optimization of Q-MRI. To accomplish this goal, B-Q MINDED proposes a collaborative cross-disciplinary approach (from basic MR physics to clinical applications) with strong involvement of industry.

Researcher(s)

• Promoter: Sijbers Jan
• Co-promoter: den Dekker Arjan
• Co-promoter: Guns Pieter-Jan
• Co-promoter: Verhoye Marleen

Research team(s)

• Vision lab

Project website

Project type(s)

• Research Project

Abstract

EGAMI stands for Expert Group Antwerp Molecular Imaging. Moreover, EGAMI is the mirror word of 'image'. EGAMI clusters the internationally recognized expertise in the profession of fundamental and biomedical imaging at the University of Antwerp: the Bio-Imaging Lab, the Molecular Imaging Center Antwerp (MICA), Radiology, the Laboratory for Cell Biology and Histology, and the Vision Lab (for post-processing of medical images). EGAMI's mission is providing an integrated research platform that comprises all aspects of multimodality translational medical imaging. Multimodality refers to the integration of information from the various imaging techniques. Within EGAMI, there is pre-clinical and clinical expertise and infrastructure for magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography (PET), and single-photon emission computed tomography (SPECT). EGAMI executes projects ranging from applied biomedical (imaging) and fundamental research to imaging methodologies. Die applied biomedical research focusses on the research fields neuro(bio)logy (i.e. development and validation of biomarkers (as well as therapy evaluation) for diseases like Alzheimer's, schizophrenia, multiple sclerosis etc.) and oncology (i.e. biomarkers for improved patient stratification and therapy monitoring). Since the pre-clinical biomedical research within EGAMI makes use of miniaturized versions of imaging equipment for humans (scanners) is it inherently translational, in other words initial findings acquired in animal experiments can be translated into clinical applications for improved diagnosis and treatment of patients ('from bench to bedside'). Beside the application of imaging in the biomedical research, EGAMI also conducts projects that aim to achieve an improvement and optimization of the imaging methodology. The expertise of the MICA (e.g. the development of new radiotracers) and of the Vision Lab (e.g. the development of image reconstruction, segmentation, and analysis algorithms) offers here the strategic platform to assemble intellectual property rights.

Researcher(s)

• Promoter: Van Der Linden Annemie
• Co-promoter: Parizel Paul
• Co-promoter: Sijbers Jan
• Co-promoter: Staelens Steven
• Co-promoter: Timmermans Jean-Pierre
• Fellow: Guns Pieter-Jan
• Fellow: Lanens Dirk
• Fellow: Van Putte Wouter

Research team(s)

• Bio-Imaging lab

Project type(s)

• Research Project

Abstract

A vast increase in elderly people represents an expanding socio-economic burden and leads to new medical challenges. In the cardiovascular system, aging causes stiffening of the heart and vasculature, providing a background for diseases. The aging process is incompletely understood and new insights are needed to improve preventive and therapeutic strategies. This project unravels the role of two growth factor signaling pathways, insulin-like growth factor (IGF) and neuregulin-1 (NRG1)/ErbB, in age-related cardiovascular impairment. The cardioprotective nature of these pathways has been described in several conditions. Surprisingly, a decrease in IGF has been associated with longevity. To unravel this paradox, we examine the behavior and function of IGF and NRG1/ErbB signaling in an aging mouse model that displays early onset of age-related cardiovascular impairment. First, senescence-prone mice will be subjected to life-style risk factors that aggravate the course of their cardiovascular dysfunction. Changes in IGF and NRG1/ErbB signaling will be characterized. Next, we will activate and inhibit these pathways in vivo using recombinant proteins and specific receptor inhibitors respectively to examine whether the aging phenotype is accentuated or soothed. In the last part of this study, the question is addressed whether exercise training has beneficial effects via alterations in growth factor signaling. Mice will be subjected to treadmill running and randomized to receive growth factors or tyrosine kinase inhibitors. Additionally, a link between growth factor signaling and changes in miR expression (non-coding small RNAs that function as modulators of physiological processes) will be investigated. Specific miRs have been linked to aging and, interestingly, some of these appear to influence growth factor signaling. These miRs therefore bare diagnostic and therapeutic potential. In all parts of our study, changes in miR expression will be linked to growth factor signaling. A functional link can be made in a second stage using miR inhibitors or mimics. In summary, this project is the first to study the role of IGF and NRG1/ErbB pathways in age-related cardiovascular impairment. Over the past decade IGF and NRG1 came forward as powerful cardioprotective agents in conditions of heart failure and phase II clinical trials have been initiated. Uncovering the effects of IGF1 and NRG1 in the aging cardiovascular system is clinically very important.

Researcher(s)

• Promoter: Guns Pieter-Jan
• Promoter: Lemmens Katrien
• Fellow: Shakeri Hadis

Research team(s)

• Physiopharmacology (PHYSPHAR)

Project website

Project type(s)

• Research Project

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: Van Der Linden Annemie
• Co-promoter: Adriaensen Dirk
• Co-promoter: Timmermans Jean-Pierre
• Fellow: De Visscher Geofrey
• Fellow: Guns Pieter-Jan

Research team(s)

• Bio-Imaging lab

Project type(s)

• Research Project

Abstract

Recently it has been suggested that purinergic (P2) receptors exert a role in the pathogenesis of atherosclerosis. ATP, UTP, ADP and UDP are the natural agonists for P2-receptors. P2-receptors can be divided in two families with different subtypes: P2X(1®7) and P2Y(1®13). P2X-receptors are ligand-gated ion channels made by the assembly of subunits. P2Y-receptors are, via G-protein, coupled to phospholipase C or adenylate cyclase stimulation/inhibition. Vascular endothelial cells, as well as smooth muscle cells, macrophages and platelets express one or more subtypes of P2-receptors. Because it is difficult to study the pathogenesis of atherosclerosis in humans, a great part of our knowledge is based on the study of animal models like the apolipoprotein E-deficient (apoE-/-) mouse, which spontaneously develops atherosclerotic plaques as result of high cholesterol levels. The aim of this project is to characterise P2-receptors in the vessel wall of the mouse and to determine the role of P2-receptors in the process of atherosclerosis, using both in vitro and in vivo tests. This study may also provide future leads for farmaco-therapeutic strategies with P2-receptor antagonists.

Researcher(s)

• Promoter: Bult Hidde
• Fellow: Guns Pieter-Jan

Research team(s)

Project type(s)

• Research Project

Abstract

Recently it has been suggested that purinergic (P2) receptors exert a role in the pathogenesis of atherosclerosis. ATP, UTP, ADP and UDP are the natural agonists for P2-receptors. P2-receptors can be divided in two families with different subtypes: P2X(1®7) and P2Y(1®13). P2X-receptors are ligand-gated ion channels made by the assembly of subunits. P2Y-receptors are, via G-protein, coupled to phospholipase C or adenylate cyclase stimulation/inhibition. Vascular endothelial cells, as well as smooth muscle cells, macrophages and platelets express one or more subtypes of P2-receptors. Because it is difficult to study the pathogenesis of atherosclerosis in humans, a great part of our knowledge is based on the study of animal models like the apolipoprotein E-deficient (apoE-/-) mouse, which spontaneously develops atherosclerotic plaques as result of high cholesterol levels. The aim of this project is to characterise P2-receptors in the vessel wall of the mouse and to determine the role of P2-receptors in the process of atherosclerosis, using both in vitro and in vivo tests. This study may also provide future leads for farmaco-therapeutic strategies with P2-receptor antagonists.

Researcher(s)

• Promoter: Bult Hidde
• Fellow: Guns Pieter-Jan

Research team(s)

Project type(s)

• Research Project