Title Promoter Affiliations Abstract "Development and validation of high-definition numerical methods for mechanical design under manufacturing process variation" "David Moens" "Mechanical Engineering Technology, De Nayer (Sint-Katelijne-Waver) Campus" "The objective of this project is to develop new techniques for uncertainty quantification in FE models used for mechanical design, and to apply those to model manufacturing variability. All developments in the project will be done in the perspective of their application in this mechanical engineering context. The considered uncertainty relates to geometric and material properties of mechanical components caused by typical mechanical manufacturing processes, and the considered FE analysis types are all related to the simulation of mechanical behaviour." "The identification and validation of genetic variation associated with progressive juvenile nephropathy and tricuspid valve dysplasia." "Luc Peelman" "Department of Veterinary and Biosciences" "In this project, we focus on the identification of the genetic basis of a kidney disorder (progressive juvenile nephropathy) and a heart disorder(tricuspid valve dysplasia) in the dog. Both are spontaneous models for Alport syndrome and tricuspid valve dysplasia in humans, respectively." "Development of a CFD tool and associated experimental validation validation" "Erik Toorman" "Hydraulics and Geotechnics, Universiteit Gent" "In navigation areas with bottoms covered by a thick fluid mud layer, deep-drafted ships may be allowed to sail at a limited vertical distance above the mud-water separation , and sometimes ships even sail through the mud. This causes a very intense interaction between the water column, the mud layer and the ship. The purpose of this project is to develop a numerical methodology to calculate the interaction between water, mud and a moving object, which will lead to a better understanding of the physical reality in such cases.The project also comprises laboratory tests during which either objects are towed, or ship models are navigating in the vicinity of a mud-water interface. This will not only allow a validation of the numerical method, but will also lead to the development of general formulae for estimating forces on flat plates, geometric objects, hydrofoils and ship hulls moving in or close to fluid mud. Such formulations are mostly available for this type of bodies moving in water, but not in mud which has flow properties which are much more complex compared to water.Since classical measuring techniques for water cannot be applied in dense fluid mud layers, new validation techniques are proposed and will be evaluated.The results of the project will lead to a better understanding of the propulsion and manoeuvring of ship in muddy navigation areas, but will also stimulate the development and improvement of measurement techniques and dredging methods in such areas." "Validation of a biomarker panel for the diagnosis of malignant pleural mesothelioma" "Kris Gevaert" "Department of Biomolecular Medicine" "The aim of this project is to develop a diagnostic test for lung mesothelioma based on proteins present in blood plasma. Specifically, we will look for proteins that are released when lung cells are damaged as a result of cancer development. From our previous research we have been able to demonstrate that with our highly sensitive proteomics technique we can distinguish patients with lung mesothelioma from healthy individuals based on different proteins. Before the clinical utility of this panel of proteins can be tested in a clinical trial, our results need to be confirmed in a larger group of patients and controls. This confirmation (or validation) is the focus of this project. In the future, our test can be used to detect lung mesothelioma at an early stage. Unfortunately, this form of cancer is currently often detected late, partly due to the non-specific and late-occurring complaints experienced by patients. This limits treatment options and contributes to the very low survival rate. A diagnostic test that can detect the disease at an early stage will therefore have a positive effect on the survival rate of patients with lung mesothelioma in the long term." "Methods and tools for supporting the use, calibration and validation of traffic simulation models" "Tom BELLEMANS" "Transportation Behaviour, Business Informatics, Data-analysis and Modelling" "A COST action is an network centered around natonally funded research projects in fields that are of interest to at least five COST countries. The main objective of this Action is to develop, implement and promote the use of methods and procedures for supporting the use of traffic simulation models, especially on the topics of model calibration and validation.To this date, the bulk of resources and effort in the field of traffic simulation have focused on model development, leading to many simulation models being available on the market. These models are extensively used in applications that have great potential impact on the safety, capacity and environmental efficiency of the road system. However the fidelity of results and conclusions drawn from a simulation study, as well as the range of possible applications the tools can reliably be used for, are questionable: the same simulation study carried out by different people, even when using the same tool, is likely to give different results. Thus, the trustworthiness of the results almost entirely depends on the ability of the model users and on their intuition. Moreover, the increasing complexity of models makes appropriate and correct use a difficult task even for experts, requiring very specific calibration and validation methodologies. For these reasons the main objective of this Action is to develop, implement and promote methodologies and procedures to support the use of traffic simulation, especially on the topics of calibration and validation. To this aim the sharing and exchanging of available traffic datasets will also be a key task of the Action." "IDENTIFICATION AND VALIDATION OF DRUG-TARGET INTERACTIONS USING CRISPR/CAS-MEDIATED GENOME EDITING" "Dirk Daelemans" "Laboratory of Virology and Chemotherapy (Rega Institute)" "Drug discovery and development are cornerstones of the pharmaceutical industry. However, these processes are difficult, time-consuming and costly. Many new drugs fail during clinical development due to insufficient demonstration of their clinical benefit and efficacy. One of the major reasons for this failing is the lack of robust understanding of a drug’s mechanism of action. In addition, phenotypic drug discovery is experiencing a revival due to disappointing results obtained through target-based drug discovery. However, phenotypic drug discovery requires challenging target deconvolution approaches to identify the cellular target of a drug. Thus, the requirement of unraveling drug-target interactions to support the drug development process is greater than ever. Many methods are available to identify drug-target interactions, although none provides a one-size-fits-all solution. Genetic approaches in particular provide strong evidence for target confirmation as they examine drug-target interactions in a living cell. Although genetic approaches for target confirmation are widely applied to simple organisms, their application to mammalian cells has been hindered for a long time. Fortunately, chemical-genetic approaches in a mammalian context have started to develop with the advent of next generation sequencing technologies, RNA interference and more recently, CRISPR/Cas-mediated genome editing. However, current chemical-genetic approaches for higher eukaryotes are often plagued by technical issues, are not well suited to probe essential genes or require costly whole-exome sequencing combined with complex bio-informatics. Therefore, the field would benefit from new approaches that can simplify drug mechanism of action studies in a mammalian context. In this thesis we explore whether CRISPR/Cas genome editing can provide such an alternative for identification of drug-target interactions in a human context.In the first part we validated the cellular drug-target interaction of selective inhibitors of nuclear export (SINE). These small molecule inhibitors show potent anticancer activity in a variety of in vitro and in vivo models of cancer and are currently being tested in clinical trials against cancer. They have been shown to modulate the activity of the Exportin-1 (XPO1) protein through covalent interaction with XPO1’s cysteine528 residue. XPO1 is an essential protein of the karyopherin-β family of nuclear transport receptors and is required for the active nuclear export of many proteins from the nucleus to the cytoplasm. Inhibition of XPO1 function is considered a potential anticancer strategy. However, the direct causality between the observed anticancer activity of the SINE and the binding of the SINE to XPO1 has not been demonstrated. To validate this drug-target interaction we applied CRISPR/Cas9-induced homology directed repair to generate XPO1 mutant cancer cell lines that carry a serine substitution of the cysteine528 residue. These mutant cell lines were highly resistant to treatment of the SINE on various parameters and our results validate the anticancer activity of these inhibitors is caused by selective binding to the cysteine528 residue of XPO1.In the second part we developed a new genetic target deconvolution method based on CRISPR/Cas-mediated genome editing. We reasoned that targeted CRISPR/Cas-induced DNA double strand breaks can be utilized for rational mutagenesis to derive gain-of-function drug resistance mutations, even in essential genes. We validated this concept using three anticancer drugs for which the drug-target interactions are well-known. We then applied this concept on a large scale to scan multiple genes simultaneously and identified nicotinamide phosphoribosyltransferase (NAMPT) as the cellular target protein of an investigational anticancer compound. We further validated this drug-target interaction by X-ray crystallography and CRISPR/Cas validation experiments. Finally, we show that the CRISPR mutagenesis approach is compatible with the class 2, type V CRISPR AsCpf1 endonuclease, increasing the resolution of the methodology. Taken together, our results highlight CRISPR/Cas-mediated genome editing provides a powerful tool for the validation and identification of drug target interactions in a human cellular context." "Validation of Actionable Genomic ABerrations in a paediatric Oncology Network for Doctorate students" "Franki Speleman" "Department of Biomolecular Medicine" "High-risk neuroblastoma (HR-NB) patients undergo intensive multi-modal treatment, with over half succumbing to their disease. HR-NB cells exhibit replicative stress, and targeting DNA damage response (DDR) pathways represents a viable therapeutic option. Pharmalogical CDK12 inactivation leads to downregulation of DDR genes, selectively reducing viability of NB cells. A novel zebrafish HR-NB xenograft model for high-throughput compound testing is under development!" "Validation of new blood-brain barrier passing ferroptosis inhibitor." "Emily Van San" "Cell death signaling (CDS)" "The detrimental role of iron in organ damage and neurodegenerative processes has been known for decades. Recently, an iron-catalyzed type of cell death was conceptualized as ferroptosis or ''biological rust''. This mode of cell death is characterized by the generation of redox-active iron that promotes excessive lipid peroxidation of the cell membrane followed by leakage of the cellular content and eventually cell death. Ferroptosis has a high affinity to occur in polyunsaturated fatty acids (PUFAs) and can be induced by the inactivation of glutathione peroxidase 4 (GPX4), a lipid recovery enzyme or by depleting its essential co-factor, glutathione (GSH). The central nervous system is particularly vulnerable to ferroptosis as it is enriched in PUFA-containing phospholipids, functions highly dependent on iron homeostasis, and has relatively poor antioxidant defense mechanisms. Plenty of reports propose the contribution of ferroptosis in neurological disorders, despite no ferroptosis inhibitors have been reported yet that cross the blood-brain barrier and directly target the brain. Recently, phenothiazines, which are often used as antipsychotics, have been recognized as strong radical-trapping agents with potential ferroptosis-inhibiting capacity. Therefore, we have generated, validated, and patented a series of phenothiazine analogues showing favorable physicochemical properties for blood-brain barrier passage. Preliminary stability and in vitro tests brought forward the most potent ferroptosis inhibitor, UAMC-5172, to screen in an extensive pharmacokinetic in vivo validation. The efficacy of UAMC-5172 will be evaluated in brain-specific GPX4 null mice (Gpx4NEUKO), a preclinical model of ferroptosis-induced neurodegeneration. Accompanied by signatures of cell death and lipid peroxidation, Gpx4NEUKO mice reflect severe motoric dysfunction shortly after knock-out induction. This study should identify a novel therapeutic candidate and provide new future research opportunities for ferroptosis therapy in preclinical models for neurodegenerative diseases." "Validation of CCR8 agonism as therapeutic strategy for treatment of (auto-)inflammation" "Susan Schlenner" "Adaptive Immunology, Laboratory of Virology and Chemotherapy (Rega Institute), Sustainable Chemistry for Metals and Molecules" "The suppressive function of regulatory T cells (Treg) is indispensable for immune homeostasis and inflammation control. Hence, Treg present an attractive therapeutic target in (auto-)inflammatory disorders. In human, the chemokine receptor CCR8 is preferentially expressed by effector Treg. Notably, CCR8 signalling in Treg increases their function to efficiently suppress effector T cells – in inflammation but also in cancer. To therapeutically exploit this link, we will evaluate CCR8 agonism as a novel strategy for the treatment of autoimmune diseases. We have recently discovered a novel series of potent and selective CCR8 agonists. Their effect on human Treg function will be assessed using in vitro assays. Compounds with potent in vitro activity and suitable in vivo pharmacokinetic properties will be evaluated in a humanized graft-versus-host disease model. These studies shall establish a potent CCR8 agonist as clinical lead candidate for (co-)treatment of (auto)inflammation." "Development and Validation of a Codebook for Emergency Services Data Collection in Belgium." "Filip Haegdorens" "Centre for Research and Innovation in Care (CRIC)" "This project led by the University of Antwerp in collaboration with Netwerk Verpleegkunde, VVVS (Vlaamse Vereniging van Verpleegkundigen Spoedgevallenzorg), and AFIU (Association Francophone des Infirmiers d'Urgence), is dedicated to developing a National dataset for process and outcome data of emergency services in Belgium. This initiative aims to significantly enhance the operational efficiency and effectiveness of emergency services. By creating a validated Dutch codebook for a comprehensive database, the project will enable more streamlined and accurate data collection and analysis, ultimately leading to improved emergency care and patient outcomes in Belgium."