Research Vincent Segers

Abstract

Chronic inflammation plays a significant role in both the onset and progression of many diseases, including, but not limited to, cardiovascular disease, chronic infections, cancer, and inflammatory organ diseases such as COPD, NAFLD, and IBD. Furthermore, acute infections may also trigger chronic inflammation and associated long lasting sequelae. As the prevalence of these diseases is increasing in Western societies and also emerging in other regions, research in this area can have a profound societal and scientific impact. Regulated cell death, barrier dysfunction, and immune modulation are key drivers of chronic inflammatory processes (Fig. 1). There is growing evidence for a limited number of common molecular pathways underpinning the regulation of these processes, and hence for a complex interplay in their pathophysiology. In this regard, Infla-Med brings together UAntwerp's leading basic and translational researchers in these three domains to form a bench-to-bedside and back consortium. The collaboration of complementary forces has enabled scientific breakthroughs in inflammation-focused research and has proven crucial in leveraging collaborations and funding in this competitive research field. For instance, Infla-Med's first 'stage' (2016-2019) resulted in more than € 23M in awarded funding with an overall stable 45% success rate since 2016. Moreover, halfway through Infla-Med's second 'stage' (2020-2022), we have already acquired the same amount of competitive grants. In terms of excellence, Infla-Med's principle investigators have achieved remarkable success in securing large, highly competitive grants for interdisciplinary research at local (BOF-GOA/IMPULS), national (FWO-EOS, iBOF), and international (ERA.Net, Innovative Medicines Initiative, coordination of H2020-MSCA-ITN and HE-MSCA-DN projects) levels. This shows that Infla-Med has established a very high-performing synergistic research framework among its principle investigators. The next 'stage' of Infla-Med will focus on discovering additional scientific breakthroughs and increasing our involvement in leading international research networks and acquiring international excellence funding (ERC). Four key strategic decisions support these ambitious aims for Infla-Med's next stage.

Researcher(s)

• Promoter: De Meyer Guido
• Co-promoter: Caljon Guy
• Co-promoter: De Meester Ingrid
• Co-promoter: De Winter Benedicte
• Co-promoter: Francque Sven
• Co-promoter: Segers Vincent
• Co-promoter: Smet Annemieke
• Co-promoter: Vanden Berghe Tom
• Co-promoter: Van Der Veken Pieter
• Co-promoter: Wullaert Andy

Research team(s)

• Physiopharmacology (PHYSPHAR)

Project type(s)

• Research Project

Abstract

Chronic heart failure (CHF) is a prevalent and lethal disease, impacting millions of individuals annually. Despite advancements, there is a pressing need for new treatments to enhance patient survival rates and quality of life. Emerging therapeutic targets, such as the neuregulin-1 (NRG1)/ERBB4 pathway, offer potential solutions. NRG1 has demonstrated cardioprotective properties by activating the ERBB4 receptor, a receptor tyrosine kinase essential for cardiac development and the maintenance of normal cardiac function in adulthood. Various forms of recombinant NRG1 are currently undergoing clinical trials for CHF. However, these require intravenous administration, making them less than ideal for long-term treatment of chronic conditions. The development of small-molecule ERBB4 agonists could provide a more practical and effective therapy for CHF. Recently, our laboratory conducted a high-throughput screening that identified structures capable of activating the ERBB4 receptor, enhancing cardiomyocyte survival, and reducing cardiac fibrosis both in vitro and in vivo. While these findings are promising, there is a need to refine the chemical structures and properties of these compounds, expand our understanding of the underlying signaling pathways, and validate the effects of these compounds in a clinically relevant large-animal model of CHF. The overarching goals of this project are to develop potent ERBB4 agonists, study their impact on CHF progression in a large-animal model, and deepen our mechanistic understanding of the myocardial ERBB4 signaling pathway in CHF.

Researcher(s)

• Promoter: Segers Vincent

Research team(s)

• Physiopharmacology (PHYSPHAR)

Project type(s)

• Research Project

Abstract

Atrial fibrillation (AF) is highly prevalent and patients with AF have an increased thromboembolic risk compared to healthy individuals that can lead to stroke or systemic thromboembolism. Oral anticoagulants are used to prevent the occurrence of clinical thromboembolic events in AF patients with a high thrombotic risk (calculated by the CHA2DS2-VASc score). The use of oral anticoagulants, however, is accompanied by an increase in bleeding risk, especially in elderly patients and patients with comorbidities. In a recent study we showed that significant mitral regurgitation (MR) can reduce the thromboembolic risk in AF patients. The present project is designed to explore the causal relationship between MR and the prevention of thrombotic risk in AF patients. We aim to develop an experimental porcine model in order to further examine the pathophysiological effect of MR on this thrombotic risk. Subsequently, we will further extrapolate our experience in a clinical study to research the possible protective effect of MR on the thrombotic risk in humans by determining blood biomarkers before and after reduction of significant MR with the MitraClip system. We strongly believe that if we can confirm the protective effect of MR, our findings will have important clinical implications, as we believe that this protective effect is important to allow downsizing of anticoagulant treatment in AF patients who are at high bleeding risk in order to prevent serious bleeding complications.

Researcher(s)

• Promoter: Claeys Marc
• Co-promoter: Heidbuchel Hein
• Co-promoter: Segers Vincent
• Fellow: Van Laer Sven

Research team(s)

• Cardiovascular diseases (CARDIOVASC)

Project type(s)

• Research Project

Abstract

Heart failure (HF) and cancer are the two most common causes of death. An increasing number of patients suffer from both diseases. In the past, their occurrence in the same patients was exclusively attributed to shared risk factors, e.g. smoking. Recent studies have demonstrated that HF directly stimulates cancer growth in different mouse models of HF and cancer, but the underlying mechanisms are incompletely understood. An important unanswered question is whether treating HF with available therapy affect cancer progression. First, I will test the effects of currently used HF treatments in a mouse model of HF and solid cancer. I expect that specific HF therapies will slow HF-enhanced cancer growth. Second, I will test the same treatments in a mouse model of HF and spontaneously metastatic cancer. The comparison of the effects of HF treatments on solid and metastatic tumors will help to test the central hypothesis; it will provide clinicians with useful insights to select therapies for their patients, but will also be relevant to individuate the pathways involved in HF-enhanced cancer growth. Third, I will perform single-nuclei RNA sequencing of both tumors and myocardium. These experiments will reveal the underlying mechanisms linking HF to cancer thanks to the identification of receptors present on both tissues. The ultimate goal would be the identification of novel therapeutic targets, potentially helping millions of patients.

Researcher(s)

• Promoter: Segers Vincent
• Co-promoter: De Keulenaer Gilles
• Co-promoter: Van Laere Steven
• Fellow: Civati Celine

Research team(s)

• Physiopharmacology (PHYSPHAR)

Project type(s)

• Research Project

Abstract

In the first 4.5 years of my fellowship I developed 2 major research lines: The first was the screening for and development of small-molecule ERBB4 agonists. Research from our lab and others has shown that ERBB4 is cardioprotective and anti-fibrotic. At the start of this project, the only way to activate ERBB4 was by using the natural ligand. Thus, development of small-molecule ERBB4 agonists has high translational potential. The second research line focused on discovering the role of ERBB4 in atrial myopathy and atrial fibrillation (AF); this role was unknown at the start of this project. Recent data indicate that ERBB4 activation in both mouse and pig models of atrial myopathy decreases the inducibility of AF. In the next 5 years, I propose to continue and combine both research lines. I initiated a collaboration with the European Lead Factory, who performed a second high-throughput screening, leading to the discovery of new ERBB4 agonists with high potency. In the next years, we want to test the following hypotheses: small-molecule ERBB4 agonists (i) have protective effects on cardiomyocytes and antifibrotic effects on fibroblasts in vitro; (ii) are effective in mitigating heart failure after myocardial infarction in mice; (iii) do not induce tumor growth in mouse models that combine heart failure and cancer; (iv) reduce inducibility of AF in a pig model of atrial myopathy.

Researcher(s)

• Promoter: Segers Vincent
• Fellow: Segers Vincent

Research team(s)

• Physiopharmacology (PHYSPHAR)

Project type(s)

• Research Project

Abstract

Despite recent therapeutic advances, chronic heart failure (CHF) remains a common and fatal condition. Patients with CHF often have severe symptoms that limit their daily activity and result in a poor quality-of-life. New therapeutic strategies, based on new targets are needed. The signaling pathway consisting of neureguline-1 (NRG1) and its tyrosine kinase receptor ERBB4 could represent such a new target because of its pleiotropic profile and its crucial role in cardiac (patho)physiology. Therapies with recombinant NRG1 are being tested in clinical trials, in which NRG1 is administered intravenously in hospital. This project is based on the premise that small-molecule ERBB4 agonists could be more efficacious in chronic treatment regimens. Therefore, we started a FWO-funded project in 2018 with a high-throughput screening (HTS), resulting in the identification of 8 first-generation ERBB4 agonists that showed ERBB4-specificity and induced antifibrotic effects, but the potency and efficacy compared to NRG1 was relatively low. Recently, in collaboration with the European Lead Factory, we conducted an ultraHTS resulting in 7 structurally unrelated "second-generation" compounds, which are up to a 1000-fold more potent than the first-generation compounds at receptor level. Herein, we propose to study the biological effects of these ERBB4 agonists with the aim to increase our understanding of the cardiac ERBB system and to develop new HF therapies.

Researcher(s)

• Promoter: Segers Vincent
• Co-promoter: De Keulenaer Gilles
• Fellow: Cools Julie

Research team(s)

• Physiopharmacology (PHYSPHAR)

Project type(s)

• Research Project

Abstract

Recent clinical studies indicate that patients with heart failure develop cancer more frequently than patients of the same age without heart failure, indicating that heart failure could induce cancer growth. Recent experiments in animals confirmed that mice with heart failure develop more aggressive forms colon or breast cancer than mice without heart failure. The mechanisms underlying these exciting discoveries have not been determined, yet. Research into these mechanisms, however, is highly relevant, because it could provide novel insights in the pathophysiology of both disorders. The central hypothesis of the current project is that neuregulin-1 (NRG1) links heart failure to cancer. NRG1 is a endothelial-derived growth factor that is produced during heart failure and that has cardioprotective properties. NRG1 is the natural ligand of ERBB receptors—ERBB2, ERBB3, and ERBB4—which are expressed at different levels in cancer cells, and which are known as oncogenes. Blocking antibodies against ERBB2 and ERBB3 are currently used as anti-cancer drugs. We will test this hypothesis in mouse models of colorectal and breast cancer. Heart failure will be induced by ligation of a coronary artery, inducing a myocardial infarction. The role of NRG1 will be evaluated with transgenic knockout technology. We will also test the cardioprotective and pro-carcinogenic effects of administered NRG1 and specific ERBB4 agonists in these mouse models. NRG1 and ERBB4 agonists are in development for the treatment of heart failure. This project is scientifically and clinically novel for a number of reasons: it links pathophysiology of cancer to the pathophysiology of heart failure and circulatory failure. It is also important for the development of novel ERBB-based drugs for the treatment of heart failure. It will help in differentiating the growth stimulating effects of NRG1 or specific ERBB4 agonists, regardless of their cardioprotective properties.

Researcher(s)

• Promoter: Segers Vincent
• Fellow: Civati Celine

Research team(s)

• Physiopharmacology (PHYSPHAR)

Project type(s)

• Research Project

Abstract

Adults with a congenital heart disease (ACHD) have a lower functional capacity, reduced quality of life and worse prognosis compared to healthy individuals. ACHD and patients with heart failure (HF) induced by other aetiologies share many characteristics, incl. exercise intolerance, right ventricular (RV) dysfunction and increased inflammatory cytokine levels. Among the pathophysiological changes in HF, endothelial dysfunction is highlighted. However, the presence of endothelial dysfunction in ACHD is unknown as literature is limited and conflicting. I hypothesize that coronary microvascular dysfunction (CMD) is important in the pathophysiology of ACHD. I believe that multiple factors incl. genetics, underlying cardiac abnormality, history of cardiac surgery and RV overload, further aggravated by classical acquired risk factors (including overweight, hypertension and sedentary lifestyle), alter shear stress and promote systemic inflammation and endothelial oxidative stress in ACHD leading to a reduced nitric oxide bioavailability and endothelial dysfunction. As such I assume that CMD is associated with systemic endothelial dysfunction, reflecting CMD as part of a systemic microvascular disorder. I am convinced that detecting CMD is important to allow identification of ACHD with an unfavorable prognosis and that this CMD can easily be identified with adenosine-based Doppler echocardiography. Finally, the potential therapeutic effect of exercise training will be investigated.

Researcher(s)

• Promoter: Van Berendoncks An
• Co-promoter: Hens Wendy
• Co-promoter: Segers Vincent
• Co-promoter: Van Craenenbroeck Emeline
• Fellow: Vanreusel Inne

Research team(s)

• Cardiovascular diseases (CARDIOVASC)

Project type(s)

• Research Project

Abstract

Atrial fibrillation (AF) is the most common arrhythmia and a common cause of stroke, heart failure, and death. AF is induced by structural remodeling of the atria, also called atrial myopathy. Current therapy is limited to antiarrhythmic drugs and ablations, but these do not cure the disease. Since atrial myopathy is incompletely understood, we aim to define the molecular, cellular, and structural changes in atrial myopathy. To this end, we will use single-cell RNA sequencing and high-resolution microscopy on a pig model and on human atrial tissues. To integrate these diverse data sets and test their relationships in atrial myopathy that predisposes the tissue to AF, mathematical modelling approaches will be employed. Collectively, these versatile models will create a highly anticipated foundation for various applications, stretching from disease modeling to testing novel strategies for development of curative therapies for an ever-growing group of patients with AF.

Researcher(s)

• Promoter: Heidbuchel Hein
• Co-promoter: De Keulenaer Gilles
• Co-promoter: Segers Vincent

Research team(s)

• Cardiovascular diseases (CARDIOVASC)

Project type(s)

• Research Project

Abstract

Increasing evidence suggests the existence of shared pathophysiological mechanisms between cardiovascular diseases (CVD) and cancer. Historically, the association between these two disease entities has been prescribed to shared risk factors such as smoking, diabetes, obesity, etc. However, recent publications have, for the first time, provided evidence of a causal link between CVD, specifically heart failure (HF), and increased cancer growth. These new observations have led to the hypothesis that CVD may trigger or promote cancer growth. At present, the precise mechanism leading to enhanced cancer growth in the presence of HF is unknown. Secretion of factors by the failing heart has been suggested as a potential mechanism, in which the endothelium might emerge as a central player. Although a specific factor secreted by the endothelium has not yet been identified, we hypothesize that neuregulin-1 (NRG-1) could be an endothelial factor linking HF and cancer. NRG-1, up-regulated in various CVD including HF, is involved in the promotion of cardiac regeneration and repair. In addition, NRG-1 is a ligand for the epidermal growth factor receptors (ERBB) 3 and 4, which form dimers with ERBB2. ERBB2 and 3 are known proto-oncogenes involved in multiple cancers including breast and colon cancer. Currently, phase III clinical trials with NRG-1 as a potential treatment for HF are ongoing. Therefore, induction of tumor growth as a result of NRG-1 treatment is potentially a major safety issue during these clinical trials. Our objective is to unravel the role of endothelial secreted NRG-1 as a potential link between HF and cancer enhancement.

Researcher(s)

• Promoter: Segers Vincent
• Fellow: van Berlo Benji

Research team(s)

• Physiopharmacology (PHYSPHAR)

Project type(s)

• Research Project

Abstract

Atrial fibrillation (AF) is very prevalent and patients with AF have an increased thromboembolic risk compared to healthy individuals that can lead to stroke or systemic thromboembolism. Oral anticoagulants are being used to prevent the occurrence of clinical thromboembolic events in AF patients with a high thrombotic risk (calculated by the CHA2DS2-VASc score). The use of oral anticoagulants, however, is accompanied by an increase in bleeding risk, especially in elderly patients and patients with comorbidities. In a recent study we demonstrated that significant mitral regurgitation (MR) can reduce the thromboembolic risk in AF patients. The present project is designed to explore the causal relationship between MR and prevention of thrombotic risk in AF patients. We aim to develop an experimental porcine model in order to further examine the pathophysiological effect of MR on this thrombotic risk. Subsequently we will further extrapolate our experience in a clinical study to determine the possible protective effect of MR on the thrombotic risk in humans by determining blood biomarkers before and after reduction of significant MR with the MitraClip system. We strongly believe that if we can confirm the protective effect of MR, our findings will have an important clinical implication, since we believe that this protective effect is important to allow downsizing of anticoagulant treatment in AF patients who are at high bleeding risk in order to prevent serious complications.

Researcher(s)

• Promoter: Claeys Marc
• Co-promoter: Heidbuchel Hein
• Co-promoter: Segers Vincent
• Fellow: Van Laer Sven

Research team(s)

• Cardiovascular diseases (CARDIOVASC)

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

Neuregulin-1 (NRG-1) is a natural protein that activates the ErbB4 receptor. The NRG-1/ErbB4 system protects against chronic heart failure, a deadly disease. NRG-1 is currently tested in clinical trials for the treatment of chronic heart failure. Because NRG-1 is a protein, however, it has to be injected intravenously in the hospital, a fact that severely limits applicability of NRG-1 in chronic disorders. A small-molecule with the ability to activate ErbB4 could be an alternative and would allow oral administration. Currently, however, there are no small-molecule activators of ErbB4. Recently, we performed a high-throughput screening to test the ability of 10,000 small-molecules to activate the ErbB4 receptor. Based on this screening, we identified a substructure that could serve as a first scaffold for identification of other activators of ErbB4. We will use this substructure, 3-dimensional shape-based comparisons, and Machine Learning to find other potential ErbB4 activators in a commercial available collection of over 3 million compounds. Compounds will be further evaluated for potency, dose-dependency, solubility, and receptor specificity using different in vitro assays. We will also evaluate pharmacokinetics and in vitro toxicity. The best compounds of the previous steps will be tested in rodent models of heart failure. Success of this project could result in a small-molecule activator of ErbB4, which might lead to novel cures for heart failure.

Researcher(s)

• Promoter: Segers Vincent

Research team(s)

• Physiopharmacology (PHYSPHAR)

Project type(s)

• Research Project

Abstract

Neuregulin-1 (NRG-1) is the natural agonist of the ErbB4 receptor. The NRG-1/ErbB4 system has protective effects in various chronic disorders including chronic heart failure. NRG-1 is currently tested in phase 3 clinical trials for the treatment of chronic heart failure. However, recombinant NRG-1 has to be injected intravenously in the hospital, which is an issue that severely limits applicability of NRG-1 in chronic disorders. A small molecule that can act as an ErbB4 agonist could be administered orally; but currently, there are no small molecule agonists of ErbB4. In this project, we will use an assay that detects pairing of 2 subunits of the ErbB4 receptor. Binding of an agonist to one ErbB4 receptor subunit induces it to interact with its partner, resulting in a readable signal. We will use this assay to screen a chemical diversity Library consisting of 10.000 compounds at the VIB Compound Screening Facility. Hits will be further evaluated for potency, dose-dependency, solubility, receptor specificity using different in vitro assays. We will also evaluate pharmacokinetics and in vitro toxicity. We will test the compound with the highest potency and receptor specificity in validated rodent models of heart failure. Success of this project results in a small molecule agonist of ErbB4, which might lead to novel cures for various chronic diseases.

Researcher(s)

• Promoter: Segers Vincent
• Fellow: Segers Vincent

Research team(s)

• Physiopharmacology (PHYSPHAR)

Project type(s)

• Research Project

Abstract

Neuregulin-1 (NRG-1) is the natural paracrine agonist of the ErbB4 receptor. There is overwhelming evidence that the cardiac NRG-1/ErbB4 system is activated in chronic heart failure (CHF), exerting disease mitigating and regenerative effects. Based on these data from both animals and humans, NRG-1 is developed as a drug for CHF. Clinical trials are performed, and have progressed to stage III (NCT01251406, NCT1214096, and NCT01541202). In addition, there is solid evidence from animals studies that the NRG-1/ErbB4 pathway is involved in other chronic diseases, such as diabetic nephropathy, pulmonary hypertension, atherosclerosis and fibrotic disorders. All of these are common chronic disorders, and potential therapeutic targets for NRG-1. To date, the only way to activate the NRG-1/ErbB4 pathway in vivo is to inject recombinant NRG-1 (rhNRG-1) intravenously. In clinical trials, this is performed over the course of 6-8 hours, which limits applicability of rhNRG-1 in chronic disorders. A small molecule, acting as an ErbB4 agonist would circumvent the drawbacks of a recombinant protein and might be more efficacious in treatment of chronic diseases. Currently, there are no small molecule agonists of ErbB4 identified. In this project, we propose a multi-disciplinary project, including a high throughput experiment using a chemical library to identify agonists of the ErbB4 receptor (OBJECTIVE 1), to test the compound with the highest potency and receptor specificity in validated rodent models of CHF (OBJECTIVE 2), and to define specific patient populations in the heterogeneous field of cardiovascular diseases that could benefit from ErbB4 agonists by quantifying serum levels of neuregulin-1 in human patients (OBJECTIVE 3).

Researcher(s)

• Promoter: De Keulenaer Gilles
• Co-promoter: Segers Vincent

Research team(s)

• Physiopharmacology (PHYSPHAR)

Project type(s)

• Research Project

Abstract

Neuregulin-1 (NRG-1) is the natural agonist of the ErbB4 receptor. Recent evidence clearly shows that the NRG-1/ErbB4 system has protective effects in various chronic disorders including chronic heart failure, chronic diabetic kidney injury, and fibrotic disorders, such as lung fibrosis. All of these are common and deadly disorders. Recombinant Neuregulin-1 is currently tested in phase 3 clinical trials for the treatment of chronic heart failure. However, recombinant NRG-1 has to be injected intravenously in the hospital over the course of 6-8 hours, which is an issue that severely limits applicability of recombinant NRG-1 in chronic disorders. A small molecule that can act as an ErbB4 agonist could circumvent the drawbacks of a recombinant protein and might be more efficacious in treatment of chronic diseases. Currently, there are no small molecule agonists of ErbB4 identified. In this project, we propose a high throughput experiment using a chemical library to identify agonists of the ErbB4 receptor. After in-house optimization of the assay, we will screen a chemical Library consisting of 20.000 compounds at the VIB Compound Screening Facility. Solubility and receptor specificity for ErbB1, ErbB3, and ErbB4 of the hits of this screening assay will be further evaluated using western blotting and ELISA assays. We will test the compound with the highest potency and receptor specificity in validated rodent models of heart failure and fibrosis. We used these animal models before in our laboratory and we successfully showed protective effects of recombinant NRG-1 in all these models. We will also evaluate signs of toxicity in these models without performing a full scale toxicology experiment at this stage. In conclusion, there is robust evidence from our and other laboratories that recombinant NRG-1 has protective effects in various chronic diseases, but the route of administration is prohibitive for wider applicability in the clinic. If this project is successful in identifying a small molecule agonist of ErbB4, we might have the key to novel cures for various chronic diseases.

Researcher(s)

• Promoter: Segers Vincent
• Co-promoter: De Keulenaer Gilles

Research team(s)

• Physiopharmacology (PHYSPHAR)

Project type(s)

• Research Project

Abstract

Neuregulin-1 (NRG-1) is the natural activator (agonist) of the ErbB4 receptor. NRG-1 has protective effects in chronic heart failure, which is a common and deadly disorder. NRG-1 is currently tested in patients for the treatment of chronic heart failure. However, NRG-1 is a protein and has to be injected intravenously in the hospital over the course of 6-8 hours, which makes it difficult to administer NRG-1 in chronic disorders. A small molecule that activates ErbB4 similarly to NRG-1 could be administered orally and might be more effective. Currently, there are no small molecule agonists of ErbB4 identified. In this project, we propose a high throughput screening experiment using a library of 10.000 chemical substances to identify agonists of ErbB4. We will use a genetically engineered cell line that detects activation of the ErbB4 receptor upon binding of an agonist. Pairing of the receptors leads to activation of an enzyme which will generate a light emitting product. This signal can rapidly be detected by an automatic reader. After in-house optimization of the assay, we will screen a chemical Library consisting of 10.000 compounds at the VIB Compound Screening Facility. In conclusion, NRG-1 has protective effects in heart failure, but the route of administration is prohibitive for wider applicability in the clinic. If this project is successful in identifying a small molecule agonist of ErbB4, we might have the key to a new treatment for heart failure.

Researcher(s)

• Promoter: Segers Vincent

Research team(s)

• Physiopharmacology (PHYSPHAR)

Project type(s)

• Research Project

Abstract

Acute kidney injury (AKI) is a frequent and deadly complication of numerous pathological disorders. In AKI, interactions between endothelial cells, tubular epithelial cells and inflammatory cells are disturbed leading to irreversible kidney damage. Although AKI is associated with a high mortality of up to 60%, there is still no therapy for this disease. This project is based on recent observations in the Laboratory of Physiopharmacology (UA) showing previously unknown protective effects of neuregulin-1 (NRG-1) on the kidney. NRG-1 is a member of the epidermal growth factor family and has well-characterized roles in the development of the nervous system and the heart. In 2015, we discovered that activation of the NRG-1/ErbB pathway using recombinant NRG-1 protects against contrast-induced AKI in mice. In the present proposal, we describe experiments to confirm these findings and to define the mechanisms involved in the protective effects of NRG-1 on AKI. The main purpose of this proposal is to confirm the protective effects of the NRG-1/ErbB pathway in AKI and to elucidate underlying mechanisms. In order to reach this aim, we will perform multiple 'gain and loss of function' experiments in transgenic mice with cell-specific deletion of ErbB4 in endothelial cells, tubular cells, and myeloid cells. Transgenic mice and wild type littermates will be submitted to various forms of AKI, radiocontrast-induced and ischemia/reperfusion induced AKI, in presence or absence of NRG-1. The readouts of AKI will be (i) glomerular filtration rate measurements with FITC-sinistrin clearance and creatinin levels; (ii) histological assays; and (iii) measurements of mRNA expression of inflammatory mediators. NRG-1 is currently being tested in clinical trials for heart failure; the present research will reveal the therapeutic potential of NRG-1 for treatment of acute kidney injury.

Researcher(s)

• Promoter: Segers Vincent
• Fellow: Dugaucquier Lindsey

Research team(s)

• Physiopharmacology (PHYSPHAR)

Project type(s)

• Research Project

Abstract

Tissue fibrosis is a pathological scarring process disrupting normal structure and function of many organs. Recent studies reported that neuregulin-1 (NRG-1), a growth factor with cardioprotective and -regenerative properties, might play a role in fibrogenesis in heart failure and glomerulosclerosis. However, it is currently undetermined whether NRG-1 plays a general role in tissue fibrosis. We recently filed a patent claiming the use of NRG-1 to treat fibrotic disorders. In this project, we focus on preclinical studies on the effects of NRG-1 on lung-fibrosis. We will study moratility and compare the effects to Nintedanib or perfinidone.

Researcher(s)

• Promoter: Segers Vincent
• Co-promoter: De Keulenaer Gilles

Research team(s)

• Physiopharmacology (PHYSPHAR)

Project type(s)

• Research Project

Abstract

Fibrosis plays a role in the pathogenesis of many chronic diseases and is a central feature in specific disorders including scleroderma, lung fibrosis, and liver cirrhosis. There is currently no effective treatment available that halts development of fibrosis. Recently obtained preliminary data in our laboratory show that Neuregulin-1 (NRG-1) decreases fibrosis in a bleomycin-induced model of skin fibrosis. Based on these preliminary data, we hypothesize that NRG-1 plays a central – but unexplored – role in extracellular matrix biology and fibrotic diseases. NRG-1 is a proteins that plays a crucial role in development of neural and cardiovascular systems, but with an unknown role in fibrosis. The aim of this project is to confirm and expand on the in vivo anti-fibrotic effects of NRG-1 by looking at expression of extracellular matrix proteins and inflammatory cytokines. Furthermore, we will check the anti-fibrotic effects of NRG-1 on isolated fibroblasts to discriminate between direct and indirect effects. Finally, we will perform a micro-array experiment on isolated fibroblasts with or without stimulation with NRG-1 to uncover the signaling pathways involved in the anti-fibrotic effects of NRG-1. The proposed experiments will help us to confirm and expand on the preliminary findings and to determine the underlying antifibrotic pathways.

Researcher(s)

• Promoter: Segers Vincent

Research team(s)

• Physiopharmacology (PHYSPHAR)

Project type(s)

• Research Project

Abstract

Kidney failure is a frequent cause of increased morbidity and mortality. To date, no conclusive pharmacological therapies for kidney failure exist and does it frequently lead to kidney dialysis or transplantation. We recently filed a patent claiming the preventive effects of this specific protein against the development of type 1 diabetic nephropathy. We want to expand this claim to other forms of acute or chronic kidney disease.

Researcher(s)

• Promoter: Segers Vincent
• Co-promoter: De Keulenaer Gilles

Research team(s)

• Physiopharmacology (PHYSPHAR)

Project type(s)

• Research Project

Abstract

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

Researcher(s)

• Promoter: Segers Vincent

Research team(s)

• Physiopharmacology (PHYSPHAR)

Project type(s)

• Research Project

Abstract

Researcher(s)

• Promoter: De Keulenaer Gilles
• Fellow: Segers Vincent

Research team(s)

Project type(s)

• Research Project

Abstract

Researcher(s)

• Promoter: De Keulenaer Gilles
• Fellow: Segers Vincent

Research team(s)

Project type(s)

• Research Project