Research Annelies Van Eyck

Abstract

The Laboratory of Experimental Medicine and Pediatrics - within the Faculty of Medicine and Health Sciences and closely linked to the Antwerp University Hospital - focusses its research on the study of inflammation in a clinically relevant context built on interdisciplinary methodologies and collaborations. To remain in the forefront of research we perform ground-breaking experimental, as well as clinical and translational research from bench to bedside and vice versa, using innovative and high-end methodologies including organoids, rodent models, cell cultures, different next-generation omics approaches and clinical trials. We challenge you to write down a project that will have an added value to one of the research lines currently explored at LEMP (www.uantwerpen.be/en/research-groups/lemp) and briefly described below. Loss of mucosal barrier integrity is a significant contributor in the pathophysiology of mucosal inflammatory/infectious diseases (e.g. IBD, gastrointestinal cancers, RSV, COVID-19). The role of transmembrane mucins, as epithelial signalling receptors mediating barrier dysfunction, is poorly understood. Furthermore, the presence of genetic differences in mucin genes can give rise via alternative splicing to a large repertoire of structurally diverse mucin mRNA isoforms encoding similar biological functions or altering protein function resulting in progression towards disease. Currently, the mucin mRNA isoform landscape implicated in mucosal barrier dysfunction is a field to discover. Volatile organic compounds (VOCs) are compounds that are by-products of cell metabolism and induced by inflammation. The human body houses thousands of VOCs which are exhaled and can serve as non-invasive markers for disease. Hence, breathomics is applied to search for clinically relevant diagnostic, prognostic and predictive biomarkers for inflammation-related diseases in adults and children (thoracic cancers, COVID-19, asthma, COPD, BPD in neonates, gastrointestinal diseases) and to monitor the effect of air pollution on human health. However, there is a need for further identification and data mining of volatiles, linking VOCs to metabolic processes. Chronic low-grade inflammation is a key factor in obesity. As its treatment remains challenging over all age groups, research focusses on new treatment strategies for obesity, that minimize dropout and weight regain. Pathophysiological processes (hypoxia) that lead to comorbidities like cardiovascular and metabolic morbidity and obstructive sleep apnoea are also of interest. Kidney transplantation is the best treatment for patients with end-stage renal disease. As diagnosis requires invasive procedures, there is a need of sensitive, non-invasive markers of an early-stage acute rejection and the early diagnosis of glomerular damage in children and adults with various underlying diseases (diabetes, obesity or sickle cell anaemia). Visceral pain is a key feature of the gastrointestinal disorders IBD and IBS. The management of visceral hypersensitivity is challenging and requires further research towards new treatment targets. Unravelling the immunopathogenesis of chronic Hepatitis B infections is essential in the quest for novel treatment approaches. While the ineffective T-cell responses are well-known, B cells have been left largely understudied, urging a deeper understanding of the role of the humoral immune response in chronic HBV at the level of HBV-specific antibody production and of the phenotypic/functional level of B cells. Non-Alcoholic Fatty Liver Disease (NAFLD) is the global leading cause of chronic liver disease but pharmacological treatment remains poorly successful. Changes in liver hemodynamics and in parenchymal oxygenation contribute to the steatohepatitis and progressive disease worsening and are a potential drugable target. Furthermore, the role of NAFLD on extrahepatic vascular alterations contributing to cardiovascular disease warrants further study.

Researcher(s)

• Promoter: De Winter Benedicte
• Co-promoter: Lamote Kevin
• Co-promoter: Ledeganck Kristien
• Co-promoter: Smet Annemieke
• Co-promoter: Van Eyck Annelies
• Fellow: Oosterlinck Baptiste

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project

Abstract

Nonalcoholic fatty liver disease (NAFLD) is the liver component of the metabolic syndrome and reaches global epidemic proportions. Isolated steatosis is the most common form, but some patients progress towards nonalcoholic steatohepatitis (NASH). The latter predisposes to fibrosis, cirrhosis and cardiovascular disease. Determinants of progression towards NASH are unclear. In isolated steatosis, we have previously shown the presence of increased hepatic vascular resistance which potentially leads to low-flow ischemia and hepatic parenchymal hypoxia, triggering the transition to steatohepatitis. We hypothesize that this chronic hepatic hypoxia induces a specific subtype of cell death in steatotic hepatocytes, i.e. ferroptosis. This recently described cell death is mediated by iron-catalyzed membrane lipid peroxides and has been suggested to play an important role in NAFLD. We will study the presence of hepatic ferroptosis in relation to disease severity in a large human NAFLD cohort. The potential of hypoxia to induce ferroptosis will be assessed in an in vitro NAFLD model to study the trigger of ferroptosis. Furthermore, we will objectify the presence of hepatic parenchymal hypoxia and ferroptosis in a murine dietary model of NAFLD. Afterwards, we will test the potential of vasodilatory compounds (which reduce hepatic hypoxia) and a novel third-generation ferroptosis inhibitor to inhibit progression towards NASH and treat an established NASH in the murine dietary model.

Researcher(s)

• Promoter: Francque Sven
• Co-promoter: Vanden Berghe Tom
• Co-promoter: Van Eyck Annelies
• Fellow: Peleman Cédric

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project

Abstract

Obstructive sleep apnea is an important contributor of additional morbidity in obese patients. Obesity is a prevalent problem in children and adults often complicated by the metabolic syndrome. The components of the metabolic syndrome track from childhood to adulthood implicating an earlier onset of cardiovascular complications. It is therefore important to study the comorbidities that might have an additional contribution on obesity and its metabolic complications as well as the mechanism by which such interactions may contribute to metabolic dysregulation. Adipose tissue is an important factor in the development of obesity and its associated comorbidities. The pathophysiological mechanisms linking obstructive sleep apnea and the metabolic syndrome are still under investigation, but a role for adipose tissue dysfunction caused by oxygen deprivation is suggested. This translational research project will focus on the impact of obstructive sleep apnea on the adipose tissue, investigating the possible crucial role of intermittent hypoxia, both in an animal model and a clinical study in adolescents and young adults.

Researcher(s)

• Promoter: Van Eyck Annelies

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project

Abstract

Obesity and the metabolic syndrome are highly prevalent in children, adolescents and adults. It is known that the components of the metabolic syndrome track from childhood to adolescence and adulthood implicating an earlier onset of cardiovascular morbidity. This stresses the importance of early prevention and management of obesity. Unfortunately, the medical management of obesity remains challenging. It is therefore important to study certain comorbidities that might have an additional contribution on obesity and the components of the metabolic syndrome and to study the mechanisms by which such interactions may contribute to metabolic dysregulation. In this perspective, we study obstructive sleep apnea (OSA) as an important contributor of additional morbidity in obese subjects. Adipose tissue is an important factor in the development of obesity and its associated comorbidities. The adipocyte is a major source of proinflammatory cytokines and adipokines, and all of these molecules can exert potential negative or positive effects on several organ systems in an endocrine or paracrine fashion. One of the hypothesis linking OSA to adipocyte dysfunction in obese subjects is an exacerbation of the concomitant obesity-related hypoxia in the adipose tissue. In view of the high prevalence of OSA in obesity and of the established independent link between OSA and the metabolic syndrome, it is crucial to study the possible effects of OSA on the adipose tissue, as this will increase our knowledge on the pathophysiological mechanisms linking obesity, OSA and the metabolic syndrome. This translational research project will focus on the impact of OSA on the adipose tissue by investigating the possible crucial role of hypoxia on adipose tissue dysregulation. A high-fat diet mice model will be initiated to get a better understanding of the hypoxia processes during obesity, and to correlate this with obesity-related comorbidities. In parallel during a clinical study subcutaneous and visceral adipose tissue biopsies are collected during bariatric surgery in adolescents and young adults.

Researcher(s)

• Promoter: Van Eyck Annelies

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project

Abstract

Overweight and obesity in children and adolescents are prevalent, have several long lasting medical and psychosocial comorbidities and post a serious burden on society. Tackling weight problems at an early age in a sustainable way is therefore of utmost importance. Earlier studies of the UGhent and the UZA research groups, showed that in the short term a multidisciplinary obesity treatment (MOT) focusing on behavioral lifestyle approach, has a positive impact on weight and comorbidities. However, existing therapies have only limited success, specifically at long-term. One explanation for these modest results relates to poor executive functions (EFs, e.g., attention, inhibition) in overweight and obesity. EFs are needed for self-control and resisting temptation. The UGhent group investigates since 2011, as the first group worldwide, the potential of EF-training strengthening selfcontrol capacities in obese youth and proved that a computerized EF-training on top of an evidence-based MOT enhances EFs of obese youth, and increases their capability to maintain weight loss until 8 weeks after treatment. This proof-ofconcept for the present project is strengthened by recent international studies showing that training individuals to control responses to high-calorie foods via computerized tasks results in weight loss. We aim to show now that adding computerized EF-training to evidence-based MOT further improves weight maintenance until 6-month after MOT and ameliorates medical and psychosocial comorbidities. We will test this in a multicenter longitudinal, prospective randomized RCT. During the regular MOT, 200 obese youngsters (8-18 years) will be randomized on a 1/1 base to either a 6 week EF-training or an active control condition, followed by 8 weekly (training or control) booster sessions. The effects of the EF-training will be measured immediately after the MOT, at 2 month and 6 month. We expect significant effect of EF-training on 1) weight loss maintenance up to 6-months after MOT, 2) EF and 3) comorbidities and related to health benefits. The project partner's extensive professional network and close collaboration with the different partners from the advisory board (BASO, VVK and Eetexpert.be vzw) allows for the broad dissemination of the project results to different target groups. The EF-training (and manual) will be presented to different MOT centers. A train-the-trainer program will be developed. Press releases, communications to the general public and appropriate stakeholders (e.g., health authorities, medical societies and youth health organizations) and scientific presentations and publications will report on the project's activities and results.

Researcher(s)

• Promoter: Verhulst Stijn
• Fellow: Van Eyck Annelies

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project