Title Promoter Affiliations Abstract "The platelet lipidome, a key regulator of platelet inflammatory andprocoagulant functions during sepsis" "Claudia Tersteeg" "Cardiovascular Sciences, Kulak Kortrijk Campus" "Apart from their well-recognized role in arterial or venous thrombotic diseases, platelets are also activated during severe infection (sepsis) and play a key role in controlling microthrombosis and inflammatory response, a process called thromboinflammation. Lipids are the precursors of inflammatory mediators that have a recognized impact on sepsis outcome. Their platelet content and composition can be modulated by a specific enzyme. A modulation of the activity of this enzyme not only affects lipid content but concomitantly impact the activation status of intracellular proteins. Therefore, this enzyme might be a central contributor to sepsis physiopathology, especially trough the regulation of platelet procoagulant and inflammatory functions, which we aim to demonstrate in the current project. This will identify whether this pathway can be considered as a valuable therapeutic strategy to improve clinical outcomes of septic patients." "The platelet lipidome, a key regulator of platelet inflammatory and procoagulant functions during sepsis" "Sandrine Horman, Claudia Tersteeg" "Cardiovascular Sciences, Kulak Kortrijk Campus" "Apart from their well-recognized role in arterial or venous thrombotic diseases, platelets are also activated during severe infection (sepsis) and play a key role in controlling microthrombosis and inflammatory response, a process called thromboinflammation. Lipids are the precursors of inflammatory mediators that have a recognized impact on sepsis outcome. In this project, we will decipher the role of modulating lipid synthesis/composition and protein acetylation in a mouse experimental model of endotoxemia. This will identify whether modulating de novo lipogenesis can be considered as a valuable therapeutic strategy to improve clinical outcomes of septic patients." "Generation and characteristics of procoagulant platelets" "Claudia Tersteeg" "Cardiovascular Sciences, Kulak Kortrijk Campus" "Upon activation, a subpopulation of platelets adopts a necrotic procoagulant phenotype, which is characterized by bioenergetic failure of the cell. The molecular events underlying the formation of procoagulant platelets include calcium cytotoxicity and reactive oxygen species; both facilitate the cyclophilin D (CypD)-dependent formation of the mitochondrial permeability transition pore, leading to a decreased mitochondrial membrane potential and ATP depletion. Our research is focusing on better understand the formation of procoagulant platelets and their pathophysiological role in thrombosis and thrombo-inflammation. For this, we are currently analyzing the role of a mitochondrial enzyme in CypD-dependent procoagulant platelet formation and hypothesize that this enzyme protects platelet mitochondria from injury mechanisms that lead to platelet bioenergetic failure and necrosis. Next, we are studying procoagulant platelet formation in different thrombotic disorders using mouse models and patient samples. And last, we are investigating specific proinflammatory mediators secreted from procoagulant platelets, and their role in thrombo-inflammation. Altogether, this will increase our fundamental knowledge on platelet death, and may eventually reveal new therapeutic targets across a range of pathological conditions." "Investigating the interplay between VWF, platelets, and neutrophil extracellular traps inpathologies involving thrombosis of the microvasculature" "Simon De Meyer" "Cardiovascular Sciences, Kulak Kortrijk Campus, Centre for Molecular and Vascular Biology" "Thrombosis is a complex process involving activation of endothelial cells, and their release of Weibel-Palade body contents such as von Willebrand factor (VWF) and P-selectin. This in turn recruits platelets which form aggregates, and leukocytes such as neutrophils. The recent discovery of neutrophil extracellular traps (NETs) described a novel antimicrobial function of neutrophils. NETs are extracellular chromatin strands containing microbicidal proteins. The release of histones, serine proteases, and myeloperoxidase concentrated on DNA fibers into the extracellular space can contribute to many pathologies. NETs can bind platelets and red blood cells and therefore also contribute to thrombosis. Activated platelets can in turn stimulate neutrophils to make NETs, creating a vicious thrombo-inflammatory cycle.Our first objective is to study VWF involvement in the induction of NETosis. We will elucidate the role of VWF as an important mediator of NET formation using VWF mutants. Innovative live-cell imaging and flow cytometry will be used to unravel the kinetics of VWF/platelet-mediated NET formation. Our second objective is to assess the physiological relevance of (inhibiting) platelet/VWF involvement in NETs-related pathology. We will investigate the role of VWF/NET interactions in three critical clinical settings where microvascular thrombosis contributes to multiorgan failure and/or mortality: sudden inflammatory response syndrome (SIRS), thrombotic thrombocytopenic purpura (TTP), and severe malaria. Mouse models of disease will be used and combined with several strategies for inhibition of VWF/platelet/NETs interactions to assess their effect on disease progression.In summary, with this research project we aim to better understand how platelets and VWF can drive NET formation in thrombo-inflammation, as this may also lead to more targeted therapeutic approaches in diseases which currently have limited treatment options." "Platelets from tissue culture, regenerative medicine for durability and customized transfusion" "Veerle Compernolle" "Department of Diagnostic Sciences, Department of Clinical chemistry, microbiology and immunology" "  ; In the future, platelets will be grown in bio -incubatoren. Such platelets will be compared in detail in this project with the current clinical gold standard: platelets prepared from whole blood donations. The objective is to at pre-clinical level, to demonstrate the efficacy of in vitro-generated platelets. Our data will be used to support clinical trials (2018-2019)." "Investigating the interplay between von Willebrand factor, platelets, and neutrophil extracellular traps in pathologies involving thrombosis of the microvasculature" "Kim Martinod" "Centre for Molecular and Vascular Biology" "White blood cells are essential for fighting infection using specific killing mechanisms. However, when these processes get activated in the absence of infection, this can cause disease. Similarly, von Willebrand factor (VWF), which serves as a sort of glue during blood clotting by sticking platelets (small blood cells) to damaged blood vessels, can also lead to disease when it gets released without injury. One of the ways that white blood cells try to fight infection is by sending out neutrophil extracellular traps (NETs), or ejecting their DNA lined with proteins that can kill bacteria. These same proteins also damage healthy blood vessels and cause them to release more VWF, which binds platelets and can lead to small blood clots. Activated platelets are one way that white blood cells can be stimulated to make NETs, and therefore this is a vicious cycle. We aim to better understand how VWF and platelets can trigger this release of NETs from white blood cells and to see if this occurs in diseases where small blood clots form in important organs leading to organ failure and sometimes death. By inhibiting these interactions in mouse experimental models, we hope to see a protective effect in disease states. We hope to gain insight into new treatments for these deadly diseases where small blood clots lead to organ failure." "Functional genomics in human blood platelets." "Hans Deckmyn" "Cardiovascular Sciences, Kulak Kortrijk Campus, Chemistry, Kulak Kortrijk Campus, Faculty of Science, Kulak Kortrijk Campus" "v\:* {behavior:url(#default#VML);} o\:* {behavior:url(#default#VML);} w\:* {behavior:url(#default#VML);} .shape {behavior:url(#default#VML);} Normal 0 21 false false false NL X-NONE X-NONE MicrosoftInternetExplorer4 /* Style Definitions */ table.MsoNormalTable {mso-style-name:Standaardtabel; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-qformat:yes; mso-style-parent:""""; mso-padding-alt:0cm 5.4pt 0cm 5.4pt; mso-para-margin-top:0cm; mso-para-margin-right:0cm; mso-para-margin-bottom:10.0pt; mso-para-margin-left:0cm; line-height:115%; mso-pagination:widow-orphan; font-size:11.0pt; font-family:""Calibri"",""sans-serif""; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin; mso-fareast-language:EN-US;} In a quest to understand the complex mechanisms by which platelets interact with healthy and/or diseased blood vessels, many large scale genomic and proteomic studies are being performed. From these, lists of thousands of known and unknown genes/proteins have been generated, for many of which the specific function in different haemostatic processes is unknown. In this project we intend to generate genetically modified (with silenced/overexpressed genes of interest) human platelets by transplantation of lentiviral vector transduced human CD34+ hematopoietic stem cells in NOD/SCID mice. To study this, test systems will be set up to determine human platelet function in a murine background by FACS, flow chambers and in vivo thrombosis models with intravital fluorescence microscopy." "Platelets in thrombus resolution" "Claudia Tersteeg" "Chemistry, Kulak Kortrijk Campus, Cardiovascular Sciences, Kulak Kortrijk Campus" "Platelets in thrombus resolution" "Analysis of plasma, platelets and urine nucleic acids: the value of liquid biopsy to improve diagnosis, follow-up and monitoring of treatment response of lung cancer and pancreatic cancer patients." "Patrick Pauwels" "Center for Oncological Research (CORE), Molecular Imaging, Pathology, Radiotherapy & Oncology (MIPRO)" "In order to provide cancer patients with personalized treatment, molecular understanding of the tumor is indispensable. Therefore, tumor biopsies are needed. However, tissue biopsies might put the patient at risk and are encumbered by heterogeneity and suboptimal tissue acquisition. On the other hand, circulating tumor DNA (ctDNA) and RNA (ctRNA) in liquid biopsies are not only of interest during the initial work-up of a cancer patient, but also because of this approach allows monitoring of the disease during treatment, including the detection of acquired resistance, which can enable a fast switch to an alternative therapy.In this project we will evaluate the use of plasma, platelets and urine as liquid biopsy in the setting of real-time disease monitoring in a patient-friendly way. We will concentrate specifically on two tumor types with poor prognosis, i.e. non-small cell lung cancer (NSCLC) and pancreatic ductal adenocarcinoma (PDAC). Investigating urine as non-invasive sampling method and the value of liquid biopsies to monitor response to immunotherapy are two major innovative goals of this project.As the first objective, we will investigate the correlation between blood, urine and tumor tissue of NSCLC patients for the detection of targetable mutations. For the first time, real-time follow-up will be established by screening the ctDNA and ctRNA from blood and urine samples of not only EGFR mutated NSCLC patients, but also ALK- and ROS1 translocated patients during tyrosine kinase inhibitor (TKI) therapy for known and novel resistance mechanisms.Furthermore, the prognostic and predictive value of the quantification of mutated ctDNA and ctRNA in blood and urine will be examined. As the second objective, KRAS mutated NSCLC patients as a non-targetable mutation will be included in order to correlate the mutational status of blood, urine and tumor tissue. The innovative aspect is that both patients undergoing surgery with curative intent and patients undergoing chemotherapy will be included. Furthermore, a proof-of-concept study with blood and urine samples from PDAC patients before and during neoadjuvant therapy and pre- and post-surgery will be performed to assess the necessity and success of the therapy. The third objective is to develop liquid biopsy-based assays inn order to monitor the immune system and tumor load during immune therapy, which is now hampered by the concept of pseudoprogression and the lack of reliable biomarkers. At the moment there are no reliable data on the evolution of tumor necrosis during immune therapy. We will evaluate if monitoring immune makers and proliferation via liquid biopsy can predict which patients benefit of this costly therapy.To conclude, the results of this study will boost implementation of liquid biopsies (plasma and/or urine) in routine clinical care to facilitate personalized treatment of cancer patients." "Elucidating the thromboinflammatory role of platelets in ischemic stroke" "Simon De Meyer" "Cardiovascular Sciences, Kulak Kortrijk Campus" "Ischemic stroke is caused by a blood clot occluding a cerebral blood vessel. As the brain is highly dependent on a constant supply of oxygen and nutrients, the culprit clot needs to be removed as soon as possible to restore blood flow and protect the brain from further damage. However, despite significant improvement of treatment guidelines, reperfusion therapy is only available to approximately 10% of ischemic stroke patients. Moreover, although recanalization of the occluded cerebral artery is essential to salvage the threatened ischemic brain, reperfusion of the ischemic brain itself can also exacerbate tissue damage by a phenomenon called ‘reperfusion injury’. Hence, there clearly exists a pressing demand for innovative strategies to improve stroke treatment.Recently, it has become clear that both thrombotic and inflammatory pathways contribute to the pathophysiology of ischemic stroke. Additionally, emerging insights indicate an important link between these thrombotic and inflammatory pathways in stroke, which led to the concept of thromboinflammation. The main objective of this research proposal is to dissect new mechanisms of thromboinflammation in ischemic stroke, and identify novel therapeutic avenues for ischemic stroke. Successful results can open the door to larger translational and clinical studies. Better acute stroke treatments would have a tremendous impact on the direct physical health and the overall quality of life of many ischemic stroke patients."