Research projects
This section introduces all current projects of the Bioinformatics Core group.
EU projects
| Organising Knowledge about Neurodegenerative Disease Mechanisms for the Improvement of Drug Development and Therapy (AETIONOMY) |
| In January 2015 the AETIONOMY consortium started a project aiming to develop a new way to classify Alzheimer’s and Parkinson’s disease. The 5-year-project is funded by the Innovative Medicines Initiative (IMI), a joint undertaking between the European Union and the pharmaceutical industry association EFPIA. The new classification will be generated using data derived from a wide range of new biological approaches and will be based on the underlying causes of the disease. Currently, Alzheimer’s disease and Parkinson’s disease are classified by their symptoms and severity but it is clear that this does not represent the many different causes of these diseases. It has been widely recognised that within these broad disease groups there are sub-groups where the different causes result in the symptoms of memory loss or movement disorder. Funding body: Innovative Medicines Initiative (IMI) Coordinator: Prof Duncan McHale, UCB Pharma, Belgium Official website: http://www.aetionomy.eu |
| Development of novel treatment strategies based on knowledge of cellular disfunction (Beta-JUDO) |
| The main aim of the betaJUDO project is to develop innovative therapeutic strategies by increasing pharmacology-based alternatives targeting insulin hypersecretion for the treatment of young obese individuals. Evaluation will de done of current and novel therapies of intervention for their effect on counteracting insulin hypersecretion to halt destruction and facilitate recovery of functionally impaired beta-cells and brown adipocytes. Clinical characterization including validation of novel genetic variants of the young obese individuals belonging to different European cohorts and a well characterized cell model of dysfunction with isolated human palmitate-treated islets will form the basis of the translational work, where principles of reduction of insulin hypersecetion will be mechanistically dissected in the human islets and then tested in the human. Funding body: Collaborative Project of the European FP7-HEALTH.2011.2.4.3-2 program Coordinator: Prof Peter Bergsten, University of Uppsala, Sweden Contact person: Kirsten Roomp Official website: http://www.betajudo.org |
| Biomarker Development for Postoperative Cognitive Impairment in the Elderly (BioCOG) |
| Postoperative delirium (POD) is characterized by the progressive deterioration of sensory/cognitive function after surgery with incidences of up to 30-80%. It is frequently followed by postoperative cognitive dysfunction (POCD) which tends to persist over time. In elderly patients, POCD resembles chronic dementia and appears to accelerate the cognitive decline in Alzheimer dementia. POD is strongly associated with subsequent dementia after 3.2 and 5.0 years of follow-up: odds ratio = 12.52 [95% CI, 1.86-84.21] corrected for baseline dementia, severity of illness, age. In an aging society like the EU, the socioeconomic implications of POD/POCD are therefore profound. At present no treatment exists and there are no established molecular or imaging biomarkers that allow risk and clinical outcome prediction. We will establish valid biomarkers panels for risk and clinical outcome prediction of POD/POCD in N=1200 surgical patients according to the regulatory requirements of the European Medicines Agency. Thus, a valuable database will be created not yet existing worldwide. Funding body: The European Union Seventh Framework Programme (FP7) Coordinator: Dr Georg Winterer, Charité, Germany Official website: http://www.biocog.eu |
| Functional Genomic Variation in the Epilepsies (EuroEPINOMICS): Complex genetics of idiopathic epilepsies (CoGIE) |
| Idiopathic generalized epilepsy (IGE) and Rolandic epilepsy (RE)/centro-temporal spikes (CTS), the two most common idiopathic epilepsy syndromes represent prototypes for common diseases with complex inheritance. Rare mutations (mainly in ion channels) and different microdeletions (in up to 3% of IGE) have been identified as risk factors in both diseases, but the vast majority of the underlying genetic variation remains to be identified. The objective of CoGIE is to unravel the genetic basis and pathophysiology of IGE and RE establishing a unique interdisciplinary research network of clinicians, geneticists, biostatisticians, physiologists and neuroanatomists. By using a combination of modern genetic techniques, comprehensive biostatistical analysis and subsequent functional analysis of selected genes and mutations, CoGIE aims to reveal new pathophysiological pathways of common idiopathic epilepsy syndromes. Funding body: European Science Fundation EuroEPINOMICS Coordinator: Prof Holger Lerche, Hertie Institut für Klinische Hirnforschung, Universitätsklinikum Tübingen, Germany Contact person: Roland Krause Official website: European Science Foundation: CoGIE |
| Epilepsy Pharmacogenomics: delivering biomarkers for clinical use (EpiPGX) |
| The purpose of the project is to identify genome-based biomarkers for use in clinical practice to individualise treatment of epilepsy, and stratify patients for clinical trials, aiming to avoid chronicity, prevent relapse and reduce adverse drug reactions (ADRs). The project will use genome-wide analyses, including next-generation sequencing, in large, well-phenotyped patient cohorts to identify genome-based biomarkers, to improve use of current antiepileptic drugs (AEDs) and identify new therapy targets. SMEs, which are central to this project, will be able to take the data forward for development of clinical tests. Funding body: The European Union Seventh Framework Programme (FP7/2007-2013) Coordinator: Prof Sanjay Sisodiya, University College London, United Kingdom Contact person: Roland Krause Official website: http://www.epipgx.eu |
| European Translational Information and Knowlegde Management Services (eTRIKS) |
| eTRIKS is an Innovative Medicines Initiative (IMI) project addressing the knowledge management (KM) needs of the other IMI projects. IMI is Europe’s largest public-private partnership that is focused on accelerating the development of better and safer medicines for patients. Many of the IMI projects are targeting data intensive translational research requiring a KM environment that allows storing data and facilitates combined analysis of different data types. The main goal of eTRIKS is to develop a sustainable IMI translational research/KM platform and to implement a sustainable KM service for the IMI data.
tranSMART was chosen as the software basis for the development of an open eTRIKS KM platform. In addition to the software platform, we provide guidelines and data curation services as well as selection of appropriate ontologies and terminologies. This allows standardizing the data in a homogenous way and and thus guarantees better cross-study comparability. One of the goals of eTRIKS is to improve the operational efficiency in translational research by providing an adapted software and data storage environment as well as data standards. Funding body: Innovative Medicines Initiative (IMI) Coordinator: Prof Yi-Ke Guo, Imperial College, London, United Kingdom Contact person: Serge Eifes Official website: http://www.etriks.org |
International, national and LCSB projects
| MitoPD |
| Parkinson disease (PD) is an etiologically heterogeneous syndrome caused by a combination of genetic and environmental risk factors. Genetic studies point to a limited number of molecular pathways that are likely to be involved - albeit to different degrees - in different patient subgroups not only in familial, but also in sporadic PD. Converging evidence from genetic and biochemical studies indicate that mitochondrial dysfunction and ensuing cellular energy failure and oxidative stress may be one of these crucial disease pathways in a subgroup of patients. We hypothesize that we will be able to identify this subgroup by robustly discriminating a postulated “mitochondrial endophenotype” of PD from other cases - based on existing genomic and transcriptomic data derived from large, carefully phenotyped patient cohorts as well as corresponding animal and cellular models, using an integrated genomics approach. In order to achieve this, a set of first-level models will be generated from transcriptomic data from monogenic PD cases with known mitochondrial dysfunction (patients with mutations in the genes encoding parkin and PINK1) and in corresponding animal and cellular models. These models will be used as prior information for model building in larger genomic (exomes and GWAS) and transcriptomic data sets from well characterized cohorts of patients with sporadic PD, allowing us to sub-classify the cohorts according to predominant pathogenic pathways. A first-stage validation will be performed by testing mitochondrial function in patient biomaterials in sub-cohorts of patients with predicted mitochondrial phenotypes. Results of this validation step will be used to improve model generation, and validity will be confirmed in further genetically defined cohorts as well as in animal and cellular models of PD, including patient-derived induced pluripotent stem cells (iPSCs). Pathway-specific biomarkers including imaging biomarkers using MR spectroscopy will then be developed and used to define sub-cohorts. These sub-cohorts will be included in a proof-of-concept clinical trial in a double-blind randomized placebo-controlled parallel group trial using coenzyme Q10. Funding body: German Ministry for Education and Research (BMBF) "e:Med: Paving the Way for Systems Medicine"; FNR INTER Coordinator: Thomas Gasser, Hertie Institute for Clinical Brain Research, University of Tübingen and German Center for Neurodegenerative Diseases (DZNE) Tübingen, Germany Contact persons: Rudi Balling, Enrico Glaab |
| USP9 Alzheimer project - 2013 Geoffrey Beene Global Neurodiscovery Challenge |
| As part of its research focus on neurodegenerative diseases the Luxembourg Centre of Systems Biomedicine (LCSB) is investigating gender differences in the incidence and phenotypic manifestations of Alzheimer’s disease (AD). Previous research has shown that with increasing age females have a higher cumulative risk of developing AD than males. Identifying the main biomolecules involved in these specific gender differences may provide new insights on the disease aetiology and new targets for therapeutic interventions. In 2013, the institute took part in an international challenge to identify causative factors behind AD gender differences and won the “Geoffrey Beene Global Neuro¬Discovery Challenge Award” for its investigation of a potential genetic causal factor. The correspond¬ing gene, ubiquitin-specific peptidase 9 (USP9), has a gender-biased activity in the human brain and encodes an enzyme interacting with two proteins with central roles in AD (microtubule-associated protein tau (MAPT) and sirtuin 1 (SIRT1)). The joint analysis of two large-scale datasets on gene activity in post-mortem human brains from AD patients and unaffected controls showed that the Y-chromosomal copy of the gene (USP9Y) is significantly down-regulated in AD post-mortem brain samples as compared to unaffected controls, and that USP9 belongs to the genes with the largest differences between male and female brain expression levels during adulthood (without compensation of USP9Y levels by the X-chromosomal USP9X in females). To confirm the involvement of USP9 in gender-specific differences in AD and investigate the regulatory network around this gene, the LCSB has started to conduct new experiments using gene and protein expression measurements in cell culture and animal models (zebrafish and mice). Funding body: funded jointly by the BrightFocus Foundation, Geoffrey Beene Foundation Alzheimer’s Initiative and USAgainstAlzheimers Contact person: Enrico Glaab |
| Using Whole Genome Sequencing Data from LRRK2 Families to Identify Novel Rare Variants of LRRK2-associated Parkinson’s Disease |
| The age of onset and penetrance (likelihood of disease) of individuals with the LRRK2 G2019S mutation varies considerably, the latter ranging in some families from as high as 100 percent to as low as 22 percent. This variation suggests that genetic modifiers contribute to LRRK2 pathogenesis in Parkinson’s disease (PD). The objective of this project is to collect and sequence the genomes of multiple LRRK2 families and use innovative technology and computational approaches to identify and validate novel genetic modifiers of LRRK2-mediated neurodegeneration. The overarching goal is to identify genetic modifiers of LRRK2 G2019S–induced neurodegeneration in PD. To do this, researchers propose a four phase plan: Funding body: Michael J. Fox Foundation Research Grant 2013 Coordinator: Rudi Balling, Luxembourg Centre for Systems Biomedicine at University of Luxembourg Contact person: Patrick May Official website: Michael J. Fox Foundation |
| Exploring Parkinson’s Disease Inhibitor Efficacy on a Non-Dopaminergic Target (ExPDIENT) |
| Parkinson's disease (PD) is one of the most frequent age-related neurodegenerative disorders and represents a major economic and social burden for health care systems in aging societies. Although existing drug therapies, focusing on restoring dopamine levels in the brain reduced due to neurodegeneration, can alleviate some of the main symptoms, a gradual loss of efficacy and several adverse effects limit their utility. Non-dopaminergic protein drug targets are therefore being investigated to develop adjuvant treatments for currently insufficiently or inadequately addressed symptoms of PD. In this project, we will investigate a new candidate protein drug target for which double-knockout mice have been shown to be significantly less impaired in the 6-OHDA model of PD. The target has a unique tissue distribution, specificity and function and a 3D crystal structure and first inhibitors are already available. However, known inhibitors have either low binding affinity or limited bioavailability in the brain. The goal of the project is therefore to develop new high-affinity, selective and bioavailable inhibitors to pave the way for an alternative therapeutic approach. For this purpose, we will combine an in-house virtual screening pipeline with in-vitro and in-vivo experimental validation to provide a first pre-clinical proof-of-concept evaluation and efficacy testing. Funding body: Fonds National de la Recherche (FNR) Luxembourg Contact person: Enrico Glaab |
| Family Genomics |
| The decline in cost for high-throughput methodologies such as next generation sequencing (NGS) and powerful computing enables researcher to obtain genetic information from the entire genome. The availability of such methodologies requires a high sensitivity to ethical aspects. Thus, before such methodologies can enter clinical practice, they have to be developed further and experiences with NGS in clinical settings have to be acquired. We choose to investigate the genetics of diseases employing family sequencing. This offers significant benefits over sequencing cohorts of unrelated individuals, because it allows a more accurate construction of the inheritance of genetic information on every piece of the chromosomes. There are three family sequencing projects currently processed at LCSB related to Alzheimer’s disease, Cushing’s syndrome and Diabetes mellitus respectively. Funding body: Luxembourg Centre for Systems Biomedicine at University of Luxembourg (previously LCSB/ISB knowledge transfer grant) Coordinator: Rudi Balling, Luxembourg Centre for Systems Biomedicine at University of Luxembourg Contact person: Patrick May |
| Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson‘s Disease (Courage-PD) |
| Despite years of research and the considerable progress that has been achieved by identifying a number of genes and genetic risk factors for Parkinson’s disease (PD), the cause for vast majority of cases is still unknown. It is suspected that a multitude of interacting genetic and environmental risk factors, rather than single genetic mutations or single toxins, are responsible for the disease in most instances. The project Courage-PD takes an integrated approach to unravel these underlying factors. The genetic make-up of large, well-characterized patient cohorts from different ethnic populations will be deciphered. At the same time, environmental exposures will be documented, and interactions between both classes of risk factors will be elucidated using novel statistical methods. Finally, the relevance and validity of the findings will be tested in innovative cellular models, including neuronal cells, which will be generated from patient-derived induced pluripotent stem cells. We expect that this combination of state-of-the-art genetic technologies with a detailed ascertainment of environmental modifiers will provide important clues to decipher the complexity of neurodegeneration in Parkinson’s Disease. Funding body: EU Joint Programme - Neurodegenerative Disease Research Coordinator: Thomas Gasser, University of Tübingen, Germany Contact person: Marek Ostaszewski, Patrick May Official website: JPND website |
