Title Promoter Affiliations Abstract "Translational Molecular Imaging Program for the University of Antwerp: application driven preclinical research." "Steven Staelens" "Molecular Imaging, Pathology, Radiotherapy & Oncology (MIPRO)" "Given the demographic aging, research in molecular imaging has a large social support and bearing. Moreover, the successful miniaturization of (S)PE(C)T cameras these past three to five years caused a major breakthrough for small animal imaging. Dedicated high-resolution small animal imaging systems have recently emerged as important new tools for research and have entered the preclinical arena. These new imaging systems permit researchers to noninvasively screen animals for pathologies, to use various cell lines in drug and tracer development, to monitor disease progression and also response to therapy. Considerable benefits are the in vivo nature of these small animal imaging experiments enabling longitudinal studies with the animal acting as its own control, the robustness, less labour intensive biodistributions, and less sacrification of laboratory animals. This benchfee (if granted) will be applied for an integrated translational molecular imaging program for UA thereby initiating fundamental science driven by clinical questions and enabled through these preclinical research tracks. This approach efficiently closes the feedback loop to the hospital ultimately resulting in improved patient comfort." "Strategic Research Programme: Molecular Imaging and targeting of macrophages in Inflammation (ITARMI)" "Tony Lahoutte" "Cellular and Molecular Immunology, Department of Bio-engineering Sciences, Medical Imaging, Translational Imaging Research Alliance, Supporting clinical sciences" "Investigates specific biological questions in intact living subjects using non-invasive imaging based on emission tomography and optical imaging in combination with anatomical imaging (CT and MRI) and Targeting of inflammation linked to infectious diseases and cancer" "Hormones and neuroplasticity: image guided discoveries of molecular mechanisms in neuroplasticity" "Veerle Darras" "Animal Physiology and Neurobiology" "During juvenile development, male songbirds exhibit a high amount of neuroplasticity in the brain regions responsible for song learning and production, called the 'song control nuclei'. Additionally, seasonal learners display a cycle of song control nucleus growth and regression throughout a year: song control nuclei increase in volume when the days get longer in early spring and regress again when days get shorter. Both neuroplastic phenomena are associated with song learning. In zebra finches for example, developmental neuroplasticity is accompanied by the learning of a single song that does not change after they become adults. In contrast, the brain of strong, seasonal learners like European starlings becomes sensitive again to new input every spring, which is associated with song control nucleus growth. Song learning and nucleus plasticity happen more strongly or even exclusively in male birds. Both displays of neuroplasticity (developmental and seasonal) are rare in the animal kingdom and their correlation with speech learning is obvious, making it a highly interesting research topic. Despite the appeal of the phenomena as a basis for research for human applications, the molecular and cellular mechanisms underlying this type of neuroplasticity are still unclear.In this thesis we investigated the possible involvement of thyroid hormones (THs) as regulators in this learning-associated plastic process. THs are essential for many processes and not in the least for neural development, differentiation and maturation. The effects of THs in a given tissue are mainly regulated by the local availability of three types of regulators. TH transporters enable THs to cross the blood-brain barrier and to enter neurons and glial cells through their cell membrane. The four known avian TH transporters are the monocarboxylate transporters 8 and 10, the organic anion-transporting polypeptide 1C1 and the L-type amino acid transporter 1 (LAT1). Deiodinases maintain the necessary amount of active TH by converting the prohormone T4 to the bioactive hormone T3 (deiodinase type 2, DIO2), or by inactivating T4 and T3 (deiodinase type 3, DIO3). Finally, TH receptors (encoded by the THRA and THRB genes) are ligand dependent transcription factors that regulate expression of TH-responsive genes. We used in situ hybridization to study the presence of mRNA of these regulators; firstly in the developing zebra finch brain during the entire period of song learning (10 to 120 days post hatch (dph)) and secondly in the brain of seasonally learning starlings in various photoperiods: photosensitive, photostimulated and photorefractory, corresponding to winter, early spring and summer respectively.In the first part of our research, we showed that in zebra finches, DIO2 expression was high in the endothelial cells lining the brain capillaries in the entire telencephalon at 10 and 20 dph. At 30 dph, when song control nuclei are still growing but the rest of the brain has attained its mature size, DIO2 expression diminished everywhere except in HVC, RA and Area X of male birds. Said expression remained high up to 60 dph while expression in the rest of the telencephalon became undetectable. At 90 and 120 dph, when song crystallizes, DIO2 expression in the nuclei also became nearly undetectable. In females, no such local expression was observed; DIO2 expression inside the song control nuclei receded in parallel with that in the rest of the brain at 20-30 dph. Additionally, in males but not females, LAT1 expression was higher in HVC than in the rest of the brain from 30 dph up to our final sampling point at 120 dph. THRA expression was widespread and THRB expression was generally low except in RA in both sexes. Our data clearly indicate that TH regulation, of which mainly TH activation by DIO2, is gender-specific and dynamic over time during developmental neuroplasticity.Secondly, we showed that in seasonal neuroplasticity, DIO3 expression in the starling HVC was strongly elevated after 4 weeks of photostimulation compared to the photosensitive state. This was accompanied by a decrease in expression of LAT1, further substantiating that TH action is actively restricted at that point in the photostimulated state. Assuming HVC has reached its maximal size by that time, we suggest that DIO3 inhibits further TH action and thus neuroplasticity in HVC. This would help in keeping the nucleus stable during breeding, which is necessary for strong, stereotypic song. DIO2 expression was below the detection limit at all stages but may yet be expressed in HVC shortly after photostimulation and thus before our studied time point. Both THRA and THRB were expressed but the observed expression level was constant for the different photoperiods.The present results indicate that regulation of THs, mainly activation by DIO2, plays an important role in developmental neuroplasticity of the song control nuclei. Furthermore, they suggest that active inhibition of TH action by DIO3 after 4 weeks of photostimulation contributes to the stability of HVC necessary for breeding-state song. Whether DIO2 also contributes to song control nucleus growth during seasonal plasticity is yet unclear but is a promising lead for further research. Our data provide essential information on a potentially crucial mechanism in learning-associated neuroplasticity; information that will hopefully help to further elucidate the molecular machinery involved in vertebrate, and especially human, memory processing." "Combining a non-invasive multimodal imaging approach with provocative manoeuvres to improve risk prediction for sudden cardiac death in ischemic cardiomyopathy." "Olivier Gheysens" "Nuclear Medicine & Molecular Imaging" "Sudden cardiac death (SCD) by cardiac rhythm disturbances is an important cause of death in oursociety. Coronary artery disease is the most common cause of SCD. The triggers for these lethalarrhythmias are poorly understood and current risk prediction for SCD is unsatisfactory. Wehypothesize that including assessment of triggers together with a combination ofelectrocardiographic and imaging studies can improve identification of patients at risk for SCD. Wehypothesize that a sudden rise in myocardial load can trigger ventricular premature beats that candegenerate in ventricular tachycardia or ventricular fibrillation (VT/VF) in a diseased heart. Wehypothesize that remodeling of the infarcted muscle region forms the substrate for VT/VF andspecifically that fibro-fatty reorganization of the infarct border-zone induced by inflammation andthe autonomic nervous system is important in this process. We will study animal models ofmyocardial infarction with multimodal imaging techniques in vivo and perform histological analysisafter sacrifice to provide evidence for these hypotheses. The imaging techniques used in the largeanimal model will be translated in patients receiving an implantable cardioverter defibrillator forischemic cardiomyopathy. We will correlate our animal findings with the occurrence of ventriculararrhythmias in patients. The ultimate goal of our project is a better selection of patients at risk forSCD after myocardial infarction.RESEARCHMain host institution KU Leuven- 1" "ULB-VUB Joint Research Group: Brussels Diabetes Research Pole - BDRP" "Henry Heimberg" "Université libre de Bruxelles, Supporting clinical sciences, Pathology/molecular and cellular medicine" "Brussels Diabetes Research Pole is focused on studying the mechanisms of dysfunction, death and regeneration of pancreatic beta cells in diabetes and the discovery of new biomarkers for beta cell imaging in diabetes : Beta cell imaging based on novel biomarkers, specific Nanobodies, and imaging by SPECT-T; Identification and characterization of synthetic phytochemicals augmenting beta cell mass and preventing beta cell death in diabetes;Beta cell death, dedifferentiation and regeneration during diabetes;Development of iPSC cells to study monogenic forms of diabetes." "The combination of anti-angiogenic treatment with (chemo)radiotherapy in rectal tumours." "Karin Haustermans" "Laboratory of Experimental Radiotherapy" "The standard treatment for locally advanced rectal cancer is (chemo)radiotherapy followed by surgery. To increase the response to treatment, ""molecular targeted agents"" are currently being tested. These drugs targetone specific molecule in one pathway and have been thought, due to their high specificity, to be able to increase the efficiency of the treatment without increasing the toxicity for the patient. Despite the good in vivo and clinical results with some of these agents, the working mechanisms, paricularly in combination with irradiation, are poorly understood.Moreover, the response to anti-cancer treatments is very heterogeneous with some patients responding well to what is an expensive treatment andothers not at all. In the current project we will search for markers that can predict which patients will show a good response. For those patients with a less favorable response, the treatment will be optimized by the addition of inhibitors of Epidermal Growth Factor Receptor, Vascular Endothelial Growth Factor and Fibroblast Growth Factor Receptor. In our search for biological markers we will focus on biologic imaging, functional imaging and molecular/genetic characteristics of the tumor." "HERODOT. Heterogeneous quantum rod and quantum dot nanomaterials, towards a novel generation of photonic devices." "Mark Van der Auweraer" "Molecular Imaging and Photonics" "Electron hole recombination in organic materials yields a ratio 1:3 of singlet and triplet excited states. In this project we will attempt to recuperate the non-emitting tripletsby luminescent and photostable II-VI semiconductor nanoparticles (Q-dots). Several matrices, available commercially or through collaboration with other groups, will be combined with CdS- or CdSe-Q-dots (2 to 6 nm) in thin spin-coated films. The electron and hole mobility will be determined by the time of flight method in the presence and absence of Q-dots. It will be attempted to develop models to explain the experimental results and to link them to fundamental parameters such as trap depth, concentration, width of the DOS. Time-resolved luminescence of the Q-dots will yield information on the mobility of triplet excitons generated in the matrix. While the major techniques to be used are TOF, UPS and nano- or microsecond spectroscopy it is evident that where relevant morphological characterization of the films will be performed using fluorescence microscopy or atomic force microscopy." "Quantification of joint loading in adults with haemophilia using multi-segment foot modelling" "Filip Staes" "Research Group for Musculoskeletal Rehabilitation, Rehabilitation Sciences, Bruges Campus, Centre for Molecular and Vascular Biology" "Haemophilia is a rare coagulation disorder mostly affecting men. It is characterized by the absence or deficiency of circulating factor VIII (haemophilia A) or factor IX (haemophilia B). In severe cases (factor level < 1%), it could result in abnormal, sometimes spontaneous bleedings and impaired blood coagulation. Up to 90% of these bleedings occur in the musculoskeletal system, with the ankle joint being most prone to recurrent bleeding episodes. Secondary arthropathy due to recurrent ankle joint bleeds, called haemophilic ankle arthropathy, is the most disabling complication in adults with haemophilia. Yet, the functional impact of haemophilic ankle arthropathy during gait in these patients is not welldefined and the potential role of joint loading on the pathophysiological cascade remains unclear.Recent research emphasized the importance of musculoskeletal biomechanics in developing pathological/disruptive compensation mechanisms in the ankle and foot joints due to the pathophysiological cascade of haemophilic ankle arthropathy. Based on previous evidence, improvement of clinical decision-making processes in patients with haemophilic ankle arthropathy beyond current state-of-the-art can only be achieved when including dynamic biomechanical gait features assessed with 3D gait analysis. Of particular interest for these patients is the investigation of mechanical loading in the ankle and foot complex. The main objective of this project was therefore to unravel the biomechanical joint loading in adults with haemophilia using a skin marker-based multi-segment foot model.In the first, methodological part of this doctoral thesis, we substantiated the use of such a multi-segment foot model in clinical motion analysis. A current methodological challenge in multi-segment kinetic models is the partitioning of shear forces across each foot joint. As no technical devices yet exist which allow the measurement of these shear forces with an appropriate spatial resolution, the shear force partitioning currently is based on an existing proportionality scheme. The scientific community therefore claimed that these estimations might lead to measurement errors. In chapter 2, we could reject this claim as we did not find any differences between kinetic measurements obtained with the proportionality scheme and those directly obtained using an adjacent force plate method. We could therefore reliably measure ankle and foot joint biomechanics in pathological gait.We also quantified the clinical misinterpretations of earlier one-segment or rigid kinetic foot models (chapter 3). In this study it was found that one-segment kinetic foot models overestimate the ankle joint peak power generation on average 14% in pathological gait – due to an overestimation of the joint angular velocity - and future research should therefore use a multi-segment foot model to overcome this clinical misinterpretation. It is generally known that walking speed is often lowered in adult patients with haemophilia. In chapter 4 of this thesis, we confirmed that walking speed affects the multisegment foot kinetics and caution is warranted when interpreting the kinetic output of the ankle and foot joints in patients with haemophilic ankle arthropathy.In the second clinical part of this doctoral thesis, we implemented the skin markerbased multi-segment foot model to investigate the impact of haemophilic ankle arthropathy on the ankle and foot joint biomechanics during walking. In chapter 5, we established a relationship between the structural ankle joint damage (based on MRI) and the ankle joint power output in patients with haemophilia. It could therefore be concluded in this study that patients with severe blood-induced ankle joint damage have a lowered tolerance towards ankle joint mechanical loading during walking. It was also found that the biomechanical load on the ankle joint is significantly altered in PwH compared to healthy subjects, potentially triggered by the arthropathy-induced ankle joint stiffness (chapter 6). Future longitudinal studies are required to confirm this hypothesis and to determine the treatment efficacy of conservative strategies to overcome these biomechanical alterations, such as therapeutic footwear or orthopedic devices. We explored the effect of conventional footwear on the biomechanical alterations in these patients and found that these increased the ankle joint mobility and simultaneously lowered the excessive mechanical loading during mid-stance of walking (chapter 7).In conclusion, most of the biomechanical alterations during walking in patients with haemophilia were present whenever the ankle joint had existing blood-induced ankle joint damage. The clinical relevance of this project therefore dictates that haemophilia care should focus on protecting adults with haemophilia against recurrent ankle joint bleeds in order to maintain proper gait functionality. Conservative treatment strategies could be initiated with the aim to preserve or improve the ankle joint mobility, which would positively impact the ankle and foot joint biomechanics in these patients." "Structural and functional comparisons of MMP-9 forms" "Ghislain Opdenakker" "Immunobiology (Rega Institute), Molecular Immunology (Rega Institute)" "Matrix metalloproteinases (MMPs) constitute a family of soluble or membrane bound Zn2+-dependent endopeptidases. In the human species, this group contains more than 20 multidomain enzymes, including collagenases, gelatinases, metalloelastases, matrilysins, stromelysins and membrane-typeMMPs. These proteases are associated with physiological processes such as reproduction, organogenesis, bone remodeling, vasculogenesis and wound healing. Besides, they are also involved in a variety of pathologies, such as acute and chronic inflammation (e.g. rheumatoid arthritis and multiple sclerosis), cancer cell invasion and metastasis as well as cardiovascular, brain and lung diseases.MMPs are multi-domain enzymes which contain a propeptide, a catalytic domain, a Zn2+-binding domain and, in most instances, also a hemopexin-like domain. The site of active proteolysis is a combination of the catalytic domain and the Zn2+-bindingdomain which holds the active zinc ion. The hemopexin-like domain is involved in the binding of a range of proteins, including substrates, cellular receptors and TIMPs. A most studied and structurally complex memberof the MMP family is MMP-9 or gelatinase B. Although all members of theMMP family possess similar characteristics, MMP-9 is exceptional. Firstly, since MMP-9 is a gelatinase, it has an additional fibronectin-like domain which improves the ability of the molecule to bind and digest large substrates (e.g. gelatins). Secondly, MMP-9 contains a prominent O-glycosylated domain. This domain is highly glycosylated and is referred to as a flexible linker since it lends the molecule the high degree of flexibility necessary for moving along collagen fibrils. Finally, besides monomers, MMP-9 has the remarkable ability to form multimers.Literature on MMP-9 is increasing exponentially each year which makes it challenging to gain an overview on the current status of MMP-9 research. We extracted and summarized the literature highlights from the past decade. Despite the significance of MMP-9, many of its structural and functional features remain elusive. To date, the exact MMP-9 structural characterization is limited to its N-terminal and C-terminal domains and no in-depth information is available on MMP-9 multimerization. In order to clarify the structure and function of homomultimeric MMP-9, a stable full-length MMP-9 mutant was generated and produced at high yield. A protocol for separating MMP-9 monomers from multimers was optimized. A detailed analysis based on biochemical and biophysical methods yielded informationon the trimeric structure of MMP-9. Atomic force microscopic images de visu elucidated this new trimeric structure of MMP-9 multimers. Comparative analysis of structure and function revealed that TIMP-1 binds more tightly to MMP-9 homomultimers than to monomers. In view of TIMP-1-free MMP-9 secretion by neutrophils this may indicate a different functional role for MMP-9 trimers. This new insight might be critical to understand basic biological processes including inflammation, cancer cell invasion,metastasis and angiogenesis.Several MMP inhibitors (MMPIs) weredeveloped during the past 20 years. Against all odds, most clinical trials with MMPIs had poor outcomes and severe side-effects were observed. Many explanations have been postulated, but the main problem was low selectivity of the used MMPIs, which results in a disturbance of the proteolytic network and in an inhibition of antitargets. New directions for MMP targeting strategies include (i) the development of more specific MMPIs that target a single function of the MMP and (ii) the alternative use of MMPs. For the discovery of MMPIs which target distal domains, a suitable screening method has to be developed. The use of fluorogenic naturalsubstrates rather than small peptides allowed the detection of inhibitors of the fibronectin repeats, compared to small peptides. Alternative strategies for the use of MMP-9 include exploitation of the presence of active MMP-9 in diseased tissues to activate a specific drug system, as exemplified with MMP-9 substrate-loaded nanoparticles." "Drought response in Arabidopsis thaliana leaves." "Gerrit Beemster" "Integrated Molecular Plant Physiology Research (IMPRES)" "The aim of this project is to identify and functionally characterize new genes and regulatory pathways that play a role in the response of Arabidopsis thaliana to drought stress. In collaboration with the Vision lab we will develop an automated image analysis platform that will allow quantification of number, composition and size of cells in cleared leaves of 75 Arabidopsisgenotypes. The most promising lines will be analyzed in more detail."