Below is a comprehensive overview of ongoing and finished research projects of MICA:
The role of the extracellular matrix proteases MMP-9 and uPA in the development of posttraumatic epilepsy following traumatic brain injury. 01/10/2015 -30/09/2017
We propose a novel hypothesis for the development of PTE with a central role for ECM modulating components MMP-9 and uPA. TBI results in blood-brain barrier disruption, hyperexcitability and primary damage triggering repair mechanisms such as modulation of the ECM by proteases MMP-9 and uPA. These alterations in ECM proteases MMP-9 and uPA, followed by brain inflammation, induce abnormal synaptic remodeling and epileptogenesis, ultimately leading to PTE.
Imaging methodology for Huntington's disease. 01/07/2016 -30/06/2017
Prototyping and validation of a system for unrestrained awake brain PET imaging of small laboratory animals. 01/10/2015 -30/09/2016 (IOF POC)
Molecular imaging of small laboratory animals typically involves a restraining procedure to avoid movement during the imaging scan. To reduce the impact of stress, animals are anesthetized, but the latter largely influences brain physiology. The current project aims to develop a prototype for awake unrestrained small animal brain positron emission tomography (PET) imaging to better mimic the clinicalsituation where human patients are seldom sedated.
Evaluation of the role of phosphodiesterase 7 and 10 in obsessive compulsive disorders by positron emission tomography. 01/10/2015 -15/02/2016 (FWO)
Patients suffering from obsessive-compulsive disorder (OCD) present symptoms as intrusive, unwanted and recurrent thought or images (obsessions) and or repetitive behaviors (compulsions).These symptoms and behaviors become excessive and disturb significantly daily activities and lead to a low quality of life and a high burden for the family of the patient. The use of serotonin reuptake inhibitor is the most efficient strategy of treatment for OCD but 40 to 60% are refractory to this kind of drugs. So there is a need to look for new therapeutic strategies. Phosphodiesterase (PDE) 7 and 10A inhibitors has been recently proposed as potential treatment in OCD. However none study has been perform to prove this hypothesis. In vivo imaging using Positron Emission Tomography (PET) is a powerful tool to monitor the stages of disease, to study human biology, to investigate in vivo the properties of new drugs in clinical trials. This technique is quantitative and very sensitive and it is a non invasive technique which is a major advantage in brain imaging. Radiotracers are investigated to image in vivo biological targets like a receptor, an enzyme or a tumor. The aim of this project is to use PET imaging to determine the role of PDE7 and PDE10A in OCD and also verify if PDE7 and PDE10A inhibitors could be used as treatment.
Combining small animal molecular imaging with next generation neuromodulation to explore novel treatments for Obsessive Compulsive Disorder. 01/01/2015 -31/12/2017 (FWO)
In this project multimodal and multiprobe imaging techniques are applied in an animal model for obsessive-compulsive disorder (OCD) in order to investigate its neuropathophysiology without the confounding factors of human OCD research such as comorbidities and previous treatment exposure. This will allow us to identify underlying networks and the role of different neurotransmitters by in-vivo dynamic visualization of the entire brain thereby improving our fundamental understanding of the disease. Furthermore, the combination of molecular imaging with application of neurostimulation techniques such as repetitive Transcranial Magnetic Stimulation (rTMS) and Deep Brain Stimulation (DBS) in the animal model for OCD will allow optimization and evaluation of these techniques as possible treatment alternatives in later extrapolation to the clinical field.
Combining small animal molecular imaging with next generation neuromodulation to explore novel treatments for Obsessive Compulsive Disorder. 01/10/2014 -30/09/2018 (BOF)
In vivo molecular imaging is a highly sensitive tool to study in vivo neuroreceptor kinetics and to visualize entire brain network dynamics in human patients as well as in small laboratory animals. Obsessive-compulsive disorder (OCD) is a chronic disabling psychiatric disease, characterized by unwanted obsessions and compulsions to temporarily neutralize the anxiety provoked by these obsessions. The prevalence of OCD is reported to be 0.8% to 3.2% and an estimated 60% of patients remain unresponsive to medical intervention. OCD is an extremely complex psychiatric disorder resulting from a pathological interplay of serotonergic (5-HT), dopaminergic (DA) and glutamatergic neurochemical dysfunctions. In this project we have three clear objectives: 1. elucidate the pathophysiology in an animal model for OCD; 2. modulate glutamate levels for better target selection; 3. evaluate novel neuromodulation techniques miniaturized for small animals. To achieve our goals we have defined three work packages with two intermediate milestones to consolidate progress or to fall back to an alternative approach. Our first work package sets up the "compulsive checking" animal model and employs Positron Emission Tomography (PET) to visualize changes in whole brain activity (FDG μPET), serotonin (MDL μPET), dopamine (Raclo μPET) as well as glutamate transmission (by Magnetic Resonance Spectroscopy) and correlates these with symptomatic behaviour. At our first milestone after 15 months we will evaluate our findings versus existing literature and we will then decide on alternative animal models if needed. In a second work package we will challenge the animal model with glutamate-altering drugs, known to aggravate or ameliorate human OCD symptoms, in order to more specifically pinpoint a target region for neuromodulation (second milestone; mid-term). We can always fold back to targeting the nucleus caudatus. The knowledge generated (neurobiology-WP1 and target region-WP2) will then be applied in a third work package to investigate repetitive Transcranial Magnetic Stimulation (rTMS) versus gold standard intra-cortical pharmacological modulation and Deep brain Stimulation (DBS). SUMMARY: we want to exploit multimodal and multiprobe molecular imaging to investigate the neuropathophysiology of OCD in an animal model and to evaluate novel neuromodulation treatments which we miniaturized for use in rodents.
First PET-MR: A Flemish Interuniversity Research Simultaneous Time-of-Flight PET-MR scanner.
14/08/2014 -14/02/2019 (Hercules)
In collaboration with the universities of Leuven and Ghent a human TOF Pet-MR was acquired for clinical imaging research.
Biomarker based adaptive development in Alzheimer (BioAdaptAD). 01/01/2013 -31/12/2016 (IWT TBM)
The general objectives of this project are to develop a BACE inhibitor for disease modification in Alzheimer's disease and to explore the development in an earlier prodromal Alzheimer's disease population. From a drug development perspective, this will involve multiple adaptation steps and the intensive use of biomarkers.
Development of 18F-poly(2-oxazoline)-duramycin and 18Fpoly( 2-oxazoline)-RGD as radiotracers for in vivo imaging of tumor environment. 01/01/2014-31/12/2017 (FWO)
The main objective of this project is to improve the tumor targeting capability and pharmacokinetics of duramycin and RGD radiotracers using conjugation to POX for in vivo therapy evaluation in hypoxic and irradiated non small cell lung cancer. The use of a radiotracer with a better pharmacokinetic profile will result in better tumor/background ratio and faster differentiation between effective versus non-effective therapy thus in more efficient and cost-reducing personalized medicine.
Development of an in vivo microPET imaging platform for the non-invasive investigation of novel therapeutics in Alzheimer's disease. 01/01/2014-31/12/2017 (IWT-SB)
Phd project of Ann-Marie Waldron
The role of the extracellular matrix proteases MMP-9 and uPA in the development of posttraumatic epilepsy following traumatic brain injury. 01/10/2013-30/09/2015
We propose a novel hypothesis for the development of PTE with a central role for ECM modulating components MMP-9 and uPA. TBI results in blood-brain barrier disruption, hyperexcitability and primary damage triggering repair mechanisms such as modulation of
the ECM by proteases MMP-9 and uPA. These alterations in ECM proteases MMP-9 and uPA, followed by brain inflammation, induce abnormal synaptic remodeling and epileptogenesis, ultimately leading to PTE.
Development of a pre-clinical TMS coil. 01/06/2013-01/06/2015
Poxylation as next generation Pegylation. 01/02/2013-31/01/2014
The following main challenges and yet unknown biological aspects of Poxylation, that need to be addressed to demonstrate the safety as well as potential of Poxylation over Pegylation, will be the main objectives to establish the poxylation technology. Besides developing the poxylation technology, this initial project aims to develop synthetic strategies for poxylated therapeutics.
Activity-based probes for PET imaging of protease activity. 01/01/2013-31/12/2016
Proteases are important drug targets and show increasing application as biomarkers for several diseases. Non-invasive imaging of their proteolytic activity status in vivo offers tremendous potential. We will develop activity-based imaging probes targeting proteases with relevance in oncology and inflammation. These probes will be used in a two-step approach in which the pretargeting step is followed by bioorthogonal ligation with a PET label.
Design, synthesis and evaluation of new potent radioligands for PDE7 imaging and implication of PDE7 in neurological disorders. 01/10/2012-30/09/2015
The main objective of this project is to develop a PET radiotracer for PDE7 imaging. The PDE7 inhibitors will be used as lead compounds. We selected two families of compounds to increase our chances to discover a suitable PDE7 radiotracer. The structure of the compounds will be modified for labelling with 11C. Precursors for radiolabeling and the ''cold'' (non radioactive) standard compounds will be synthesized for radiotracer characterization and in vivo evaluation of PDE7 inhibitory potency and selectivity. The compounds showing the best potency (nanomolar IC50) and selectivity for PDE7 inhibition will be selected for radiolabeling. The next step will be the optimization of the radiosynthesis. The goal will be to obtain the products in a high radiochemical yield and in high radiochemical purity (> 95% for animal studies).
Preclinical investigation op PET tracers. 01/09/2012-31/08/2015
Preclinical molecular imaging using 18F-CP18 to evaluate apoptosis in vitro/in vivo and 18F-HX4 in vivo in normoxic and hypoxic tumour regions to predict outcome.
VECTor/CT: simultane PET/SPECT/CT scanner voor kleine dieren. 28/06/2012-31/12/2017
This project represents a formal research agreement between UA and on the other hand the Flemish Public Service. UA provides the Flemish Public Service research results mentioned in the title of the project under the conditions as stipulated in this contract.
Transcranial magnetic stimulation for small animals: methods and device. 01/06/2012-31/05/2013
Transcranial Magnetic Stimulation (TMS) is a treatment for various neurological disorders. We have developed a device and methods for the application of TMS in awake and freely moving small experimental animals. The project aims at performing indispensible evaluation tests and to develop a demonstrator, to support patent filing.
Immuno-positron emission tomography as a potential biomarker for diagnosis and treatment in Alzheimer disease. 01/04/2012-31/03/2014
This project represents a formal research agreement between UA and on the other hand a private institution. UA provides the private institution research results mentioned in the title of the project under the conditions as stipulated in this contract.
Investigation of functional and structural brain abnormalities utilizing multimodal brain imaging in a neurodevelopmental animal model with relevance to schizophrenia. 01/01/2012-31/12/2015
The current project will follow the development of neuroinflammation together with functional brain integrity and behavioural outcome in a rodent model of maternal immune activation in vivo utilising state-of-the-art multimodal imaging biomarkers.This project will generate highly novel information about the contribution of neuroinflammation to the development of schizophrenia and its consequences for the functional integrity of the brain, and eventually provide a rationale for the implementation of novel disease-modifying strategies.
Novel motion correction techniques for PET imaging of awake animals. 01/01/2012-31/12/2013
The overall goal of this project is to improve the quantification of PET imaging through the development and use of innovative motion correction and image reconstruction techniques.
Longitudinal in vivo follow-up of PET biomarkers in neurological disease models. 01/07/2011-31/12/2015
Chronic neurological diseases such as epilepsy and schizophrenia are difficult to manage and severely disabling disorders. Moreover, they are putting a huge burden on our social health care system. Currently, there is no available therapy that effectively halts or retards the development or progression of these conditions. The more we learn, the more it becomes clear that these neurological diseases are extremely complex as they do not have a well-understood mechanism of action and perhaps diverging dysfunctions, with evolving temporal and spatial aspects, may contribute to the disease. Remarkably, the manifestation of both diseases is preceded by a seemingly "silent" or "latent" period of several years without any apparent symptoms. Interestingly, scientific research suggests that this could be related to a neuronal insult during a critical phase of life, which initiates a series of pathophysiological processes during the latent period.
At current, little research has been directed to investigate the latent period. As in patients, the chronic stage of the disease is represented rather than the early stage, the human research endeavour has been limited due to the difficulty to set-up these type of long-term prospective studies. As a consequence, our understanding of the processes occurring during this critical phase of the development of the disorder is incomplete. For instance, it is unknown what factors contribute to the phenomenon that only a subgroup of individuals will eventually be affected by the disorder. A better insight in these events could potentially lead to early identification of patients at risk. It has been speculated that neuroinflammation plays an important role in the reorganisation of the neuronal network after the occurrence of a traumatic event. The current project will follow the development of neuroinflammation together with the investigation of the functional integrity of the brain in laboratory animals utilising imaging biomarkers. The recent advances in dedicated in vivo imaging techniques for small animal brain imaging, such as positron emission tomography (PET), allow scientist for the first time to conduct basic research in a non-invasive and longitudinal manner, facilitating translation of knowledge from bench side to clinical application.
This study will add very important new information about the contribution of neuroinflammation to the development of neurological disorders such as epilepsy and schizophrenia, its consequences for the functional integrity of the brain and whether these biomarkers could contribute to the early identification of patients as risk. Non-invasive imaging using biomarkers is an upcoming and promising new approach, which clearly allows for translation of applications to the clinic. The outcomes of this research will inform clinical practice, particularly providing rationale for the implementation of potentially neuroprotective strategies to slow down or halt this degeneration, as well as potentially providing a method to assess the biological efficacy of prospective new therapies prior to the institution of expensive human trials.
Translational Molecular Imaging Program for the University of Antwerp: application driven preclinical research. 01/10/2010-30/09/2015
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.
Translational Molecular Imaging Program for the University of Antwerp: application driven preclinical research. 01/10/2010-30/09/2013