Title Promoter Affiliations Abstract "Cross-species applicability of high throughput screening assays for thyroid hormone disruption." "Lucia Vergauwen" "Veterinary physiology and biochemistry" "There is currently an urgent need for new screening approaches to identify thyroid hormone disrupting chemicals, both in ecotoxicology and human toxicology. Toxicity testing in the 21st century increasingly relies on high throughput animal-free assays screening chemicals for their interaction with biological targets. While the thyroid system is highly conserved across vertebrate classes, conservation of the chemical susceptibility of the components of the thyroid system (enzymes, receptors) remains to be investigated. In this project, we will compare the deiodinase (the enzyme responsible for thyroid hormone (de)activation) inhibition potential of a set of test chemicals across zebrafish, pig, rat and man. This information is essential to bridge the gap between ecotoxicology and human toxicology and support the exchange of information." "The role of the paraoxonase gene family in obesity and obesity-associated liver disease following exposure to environmental pollutants or medical intervention strategies." "Wim Van Hul" "Medical Genetics (MEDGEN), Proteinscience, proteomics and epigenetic signaling (PPES), Laboratory Experimental Medicine and Pediatrics (LEMP), Proteinchemistry, proteomics and epigenetic signalling(PPES), Veterinary physiology and biochemistry, Medical genetics of obesity and skeletal disorders (MGENOS)" "Obesity constitutes a major health problem, partly due to the increasing prevalence and secondly because of its associated morbidity. It is associated with increased amounts of adipose tissue as well as fat accumulation in non-adipose tissue such as liver and skeletal muscle. Accumulation of ectopic fat in the liver (non-alcoholic fatty liver disease, NAFLD) is a strong independent marker of dyslipidaemia and insulin resistance predisposing to the development of type 2 diabetes. Besides high caloric diet and lack of physical activity, pesticide exposure and endocrine disruptor pollutants are now also increasingly recognized as an ""obesogenic"" risk factor. Remarkably, recent genome- and epigenome wide associations studies highlight crosstalk of many obesity-associated genetic variants and environmental factors (diet, pesticides, exercise, alcohol consumption, smoking, drugs, medication) with DNA methylation changes at proximal promoters and enhancers. For example, we recently found a strong association between the paraoxonase 1 (PON1) p.Q192R genotype with pesticide exposure and adverse epigenetic (re)programming of endocrine pathways in obesity and high body fat content. PON members hydrolyze several pesticides, a number of exogenous and endogenous lactones and metabolizes toxic oxidized lipids of low density lipoproteins (LDL) and HDL. A decrease in PON1 expression promotes adverse lipid metabolism and is an important risk factor for cardiometabolic disease and has recently been found to be associated with childhood and adult obesity, liver steatosis and its more severe subtype of steatohepatitis. Differences in PON2 have been associated with obesity susceptibility in brown/white adipose tissue. Given the crucial role of PON members in protecting from adverse environmental exposure and from obesity, there is an urgent need for further molecular and clinical research on (epi)genetic PON(1-3) regulation mechanisms in this area. In this GOA, we want to further investigate associations of clinical characterized obesity phenotypes with PON(1-3) genetic variants/polymorphisms, associated epigenetic DNA methylation variation and PON(1-3) expression in samples (i.e. blood, serum, adipose or liver) of clinical patient cohorts diagnosed with obesity, NAFLD/NASH, in relation to adverse pesticide exposure or following therapeutic medical intervention (liraglutide or bariatric surgery). Functional investigation of genetic-epigenetic regulatory crosstalk of PON(1-3) expression in response to pollutant exposure or following medical interventions will be further investigated in relation to biochemical parameters of obesity/liver steatosis/adipocyte differentiation in cell models in vitro as well as in zebrafish in vivo. As such, a better understanding of variable PON(1-3) regulation of obesity-associated traits by adverse obesogenic pollutants or healthy intervention strategies may offer new perspectives to prevent obesity and/or promote cardiometabolic health." "Breaking down the wall between human health and environmental testing of endocrine disrupters: EndocRine Guideline Optimisation (ERGO)." "Dries Knapen" "Ecole normale Supérieure de Lyon, University of Southern Denmark, University of Heidelberg, German Environment Agency (UBA), Masaryk University, French National Centre for Scientific Research (CNRS Paris), Leibniz-Institute of Freshwater Ecology and Inland Fisheries, Aarhus University, Yokohama City University, Helmholtz Centre for Environmental Research, Veterinary physiology and biochemistry" "ERGO presents a new approach that will support a paradigm shift in the regulatory use of standardized test guidelines (TGs) by breaking the existing wall between mammalian and non-mammalian vertebrate testing and assessment of endocrine disrupting chemicals (EDCs). The highly conserved thyroid system will be used as the ""proof of concept"", but also other conserved endocrine axes/systems such as the Retinoid X Receptor (RXR) and the Hypothalamus Pituitary Gonadal (HPG) axis can be adapted to the cross-vertebrate class approach. ERGO will investigate a battery of draft in vitro assays and evaluate thyroid-responsive biomarkers and endpoints (B/E) suitable for extrapolation of effects from fish and amphibian tests to humans and other mammals (and vice versa) and finally validate successful B/E for inclusion in existing in vivo or new in vitro OECD TGs. A cross-class adverse outcome pathway (AOP) network will provide the scientifically plausible and evidence-based foundation for the selection of B/E in lower vertebrate assays predictive of human health outcomes. In silico modeling and biotransformation data will support cross-vertebrate class effect extrapolation. Major outcomes of ERGO will be: 1) New thyroid-related B/E for inclusion in OECD TGs for improved identification of TDC. 2) An Integrated Approach to Testing and Assessment (IATA) of chemicals for TD based on a multi-class vertebrate AOP network connecting endocrine mechanisms in one vertebrate class to adverse outcomes in another class for safer regulation of EDCs. 3) A tool for TG end users, such as regulators and industry, to extrapolate thyroid effects between vertebrate classes. Implementation of the ERGO IATA strategy in regulations of EDC will make hazard and risk assessment faster, cheaper, simpler and safer and support industry in the development of EDC-free products beneficial for environmental and human safety." "The role of adipose tissue hypoxia in obesity and obstructive sleep apnea." "Annelies Van Eyck" "Laboratory Experimental Medicine and Pediatrics (LEMP)" "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." "Structural Biology of the Human Androgen Receptor for next generation drug design" "Frank Claessens" "Laboratory of Molecular Endocrinology" "The aim of this PhD project is to elucidate the mechanism of action of a novel class of human androgen receptor antagonists (MEL6), which were recently discovered in the KU Leuven Molecular Endocrinology Laboratory. Fragments of the human androgen receptor will be expressed in and purified to high purity from E. coli and utilized for crystallization experiments. While the structures of agonist complexes are already available, all efforts have failed to crystallize a complex of the hAR ligand binding domain (AR-LBD) bound to an antagonist. Therefore, we will follow a novel approach. First of all, the novel confirmed class of antagonists is significantly different in shape from the classical antagonists. Molecular modeling of AR-LBD:MEL6 complexes has suggested a binding mode that may stabilize the antagonistic conformation. Therefore, a classical co-crystallization approach will be followed. Secondly, we aim to crystallize the hAR-LBD in the presence of additional facilitator molecules, which can induce different crystal packings that may allow for soaking of antagonists or stabilization of the antagonistic conformation. These molecules are the so-called Poly-Oxometalates (POMs), which are being developed at the KU Leuven, Department of Chemistry, where also the MEL6 derivatives are being produced. Apart from the new MEL6 ligands, I will also attempt to soak the currently used drug molecules with the POM-protein crystal complexes, as structural information of them is still absent as well. In parallel with the two tracks of structural biology work, I will perform biophysical screening experiments to identify more potent ligand derivatives. As more insights are being gathered about the interactions of the N-terminus of the androgen receptor with cellular cofactors, in the final stage of this project, I will also focus on solving the structure of fragments of the androgen receptor N-terminal domain with (fragments of) its cellular cofactors." "Unraveling the ligand-independent signaling of the vitamin D receptor" "Mieke Verstuyf" "Clinical and Experimental Endocrinology" "Unraveling the ligand-independent signaling of the vitamin D receptor. The parathyroid hormone (PTH)/vitamin D axis is a major regulator in the maintenance of stable serum calcium concentrations, which is of utmost importance to ensure normal cellular and organ function. Subtle changes in circulating calcium concentrations cause an increase in the secretion of PTH which will, in turn, increase renal calcium reabsorption, enhance calcium efflux from bone and will stimulate the production of 1,25-dihydroxyvitamin D3, the active form of vitamin D3, that exerts its action by binding to the vitamin D receptor (VDR). The first major objective of this project is to delineate the physiological importance of the ligand-independent effects of VDR in parathyroid, intestine, kidney and bone. The second objective is to assess whether ligand-independent VDR signaling affects bone directly by the use of three different approaches. Those approaches will include the study of in vitro osteoblast and osteoclast cultures, the establishment of mice that express a mutant VDR∆AF2 protein in osteoprogenitors and finally the treatment of Vdr∆AF2 mice with Cinacalcet to circumvent confounding effects of PTH on bone. The third objective is to identify and characterize novel genes that are involved in calcium homeostasis by the use of a combined RNA-seq and ChIP-seq approach. " "The effects of exercise on energy expenditure and muscle function in severe burned patients." "Ulrike Van Daele" "Movement Antwerp (MOVANT)" "Severe burned patients undergo rapid increases in metabolism (hypermetabolism) and increased energy expenditure caused by the initial inflammatory and humoral responses. These responses also elicit, on top of the bed rest period, a cascade of negative reactions leading to additional muscle wasting. Muscle wasting itself leads to insulin resistance and may have long-term health consequences. Some of these effects persist from the first few days following severe burn injury to as long as three years later after wound closing. Although insulin resistance is assumed to be triggered by several catabolic factors, an important contributor to insulin resistance is muscle wasting itself. Insulin-resistance, may eventually lead to diabetes mellitus and is a long-term complication of severe burn patients which has major implications for future morbidity and mortality. Physical exercise has been shown to affects both the metabolism as well as skeletal muscle function in oncology, cardiac patients, obstructive lung diseases and diabetic patients. In addition, physical exercise in critically-ill patients has also been shown to have beneficial effects on general health outcome parameters. Therefore, in the present study we will investigate the effects of severe burns [≥ 30 % total body surface area (TBSA)] on energy expenditure, hypermetabolism (especially insulin and glucose homeostasis) and muscle function (strength). Besides the fundamental research questions we will investigate the effect of an 8 week (3 times/week) rehabilitative exercise strength training on energy expenditure, hyper metabolism and muscle function. For the long-term effects we will investigate the Quality of Life (QoL) in patients undergoing such an additional rehabilitative program on top of standard-care. For this purpose we will use both general as well as burn specific questionnaires regarding QoL." "Mobile monitoring of joint loading profiles in persons with degenerative hip and knee problems" "Annick TIMMERMANS" "Healthcare & ethics, Rehabilitation Research Center, Health Care" "Mobile monitoring of health-related parameters is a hype and can be very useful for healthcare practitioners and researchers to evaluate the efficacy of patients' treatment programs. Several cell phone applications are available to track activity parameters like heart rate, number of steps and hours of activity and rest. Their use for monitoring orthopaedic disorders of the lower limb has not yet been introduced and validated in clinical practice. However, it can be highly relevant for health care practitioners to monitor the functional outcomes in patients with musculoskeletal disorders. Mechanical loading is a contributing factor to the onset and progression of degenerative joint disease and artificial implant wear. Therefore, mobile monitoring of the evolution of a patient's total loading profile, i.e. his functional state based on an extended analysis of the activity profile, seems feasible, relevant and conceptually within reach. In this project, an integrated mobile application will be designed for monitoring and managing the loading profile in subjects with degenerative hip and knee problems prior and after surgical intervention." "Welcome Trail: improving weight control and CO-morbidities in children with obesity via executive function training." "Benedicte De Winter" "Laboratory Experimental Medicine and Pediatrics (LEMP)" "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 self-control 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-of-concept 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." "Impact of the bacterial colonic metabolism on fecal water toxicity as biomarkers of future colorectal cancer risk after bariatric surgery" "Kristin Verbeke" "Translational Research in GastroIntestinal Disorders, Clinical and Experimental Endocrinology" "Bariatric surgery is an effective way to treat obesity. Roux-en-Y gastric bypass (RYGB) reduces the gastric volume and bypasses parts of the small intestine so that malabsorption is induced whereasSleeve Gastrectomy (SG) only reduces the volume of the stomach without inducing malabsorption. Although bariatric surgery reduces overall cancer risk, evidence indicates that the risk for colorectal cancer (CRC) is increased and might depend on the type of surgery. We hypothesize that bariatric surgery modifies the bacterial colonic environment which contributes to the future CRC risk. A one-year follow-up study will be conducted in obese patients undergoing bariatric surgery and a control group of obese patients on a weight loss diet. Blood and fecal samples will be collected prior to and at specific time points after surgery or weight loss diet. We will characterize the colonic fermentation by analyzing metabolite profiles of the fecal samples, the composition of the microbiota and the bile acid composition and compare their capacity to induce toxicity in cultured colonic cells. Also the contribution of inflammation to toxicity will be taken into account. With multivariate statistical methods, we will identify those parameters that are associated with increased toxicity."