Research team

Physiopharmacology (PHYSPHAR)

Expertise

The main focus of our research is communication between endothelial cells and cardiomyocytes. More specifically, we are interested in endothelial derived proteins – such as NRG-1 – that influence cardiac function and cardiac remodeling. We are also investigating other proteins that could play a role in this communication. Furthermore, we are interested in the role of the Neuregulin-1/ErbB4 system in other organ systems and diseases such as kidneys, lungs and fibrotic disorders. The laboratory of PhysioPharmacology is one of the leading laboratories in NRG-1/ErbB4 biology. We published several manuscripts on this topic and made 5 different transgenic ErbB4 KO mice. The ultimate goal is to develop new therapies for common and deadly cardiovascular diseases.

Defining atrial myopathy in aging and disease (DIAMOND consortium). 01/01/2021 - 31/12/2024

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.

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INnovation in Safety Pharmacology for Integrated cardiovascular safety assessment to REduce adverse events and late stage drug attrition (INSPIRE). 01/01/2020 - 31/12/2023

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.

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Development of ErbB4 Agonists for Treatment of Heart Failure. 01/01/2020 - 31/12/2023

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.

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Activating the neuregulin-1/ErbB4 pathway for treatment of heart failure. 01/10/2018 - 30/09/2023

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.

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Identificatie van kleine moleculaire ErbB4 agonisten ter behandeling van cardiovasculaire ziekten. 01/09/2018 - 31/08/2022

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).

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Identification of small molecule ErbB4 agonist for treatment of heart failure, diabetic kidney injury and fibrotic disorders. 01/01/2018 - 31/12/2021

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.

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Identification of small molecule ErbB4 agonists for treatment of heart failure. 01/01/2018 - 31/12/2020

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.

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Preclinical studies on the preventive effects of neuregulin-1 in acute renal failure. 01/10/2016 - 30/09/2020

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.

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Neuregulin-1 as a preventive therapy for lung fibrosis 01/05/2016 - 30/04/2017

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.

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Preclinical studies on anti-fibrotic effects of Neuregulin-1 01/04/2016 - 31/03/2017

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.

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Research on a specific protein for the treatment of chronic and acute kidney failure. 01/12/2014 - 30/11/2015

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.

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The role of neuregulin-1 in fibrotic diseases. 01/12/2014 - 31/05/2015

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.

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The function of cardiac endothelium in myocardial regeneration. 01/10/2005 - 30/09/2007

Abstract

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    The function of cardiac endothelium in myocardial regeneration. 01/10/2003 - 30/09/2005

    Abstract

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