Gordan Lauc, PhD
Professor of Biochemistry and Molecular Biology
A. Kovacica 1, 10000 Zagreb, Croatia
Phone: +385 1 639 4467
Fax: +385 1 639 4400
Inflammatory bowel diseases affect 0.8% of the Europeans, and are associated with high morbidity, definite mortality and an increasing economic burden. Current diagnostic tools and therapeutics for IBD are unsatisfactory. Development of biomarkers allowing insights into pathogenesis, prognosis and targeted therapy is a major unmet need. This programme addresses that need. IBD-BIOM is a multidisciplinary consortium of leading academic and industrial SME researchers in inflammatory bowel disease, genomics, glycomics, glycoproteomics and activomics. Recent genome-wide association studies performed by IBD-BIOM partners have identified nearly 100 genes associated with IBD, but clinical application of these is so far limited. IBD-BIOM will capitalise on its existing high quality clinical, genetic, biochemical and immunological data and biological samples on over 6000 very well characterised IBD patients and controls by exploiting novel technological approaches made available through the expertise and global leading position of IBD-BIOM partners. These comprise cutting edge epigenetic, glycomic, glycoproteomic and activomic approaches which were all previously reported to be associated with inflammation and disturbances to the immune system. The inclusion of these complementary analyses in the diagnostics of IBD should also facilitate elucidation of pathways through which environmental exposures influence IBD risk and progression. A complex systems biology approach will be used to integrate, interrogate and understand this multidimensional dataset to identify novel early diagnostic and prognostic biomarkers and new targets for therapeutic intervention. The track record of achievement of IBD-BIOM partners coupled to the central and leading positions of the research-intensive SME partners in IBD-BIOM is a strong indication that the ambitions work programme will be achieved and a framework to facilitate swift conversion of research discoveries into commercial products.back
MIMOMICS Methods for integrated analysis of multiple omics datasets
MIMOmics develops statistical methods for the integrated analysis of metabolomics, proteomics, glycomics, and genomic datasets in large studies. Our project is based on our involvement in studies participating in EU funded projects, i.e. GEHA, IDEAL, Mark-Age, ENGAGE and EuroSpan. In these consortia the primary goal is to identify molecular profiles that monitor and explain complex traits with novel findings so far. Support for methodological development is missing. The state-of-the-art methodology does not match by far the complexity of the biological problem. Complex data are being analysed in a rather simple way which misses the opportunity to uncover combinations of predictive profiles among the omics data.
The objectives of MIMOmics are: to develop a statistical framework of methods for all analysis steps needed for identifying and interpreting omics-based biomarkers; and to integrate data derived from multiple omics platforms across several study designs and populations. Specific steps include: experimental design; pipelines for data gathering; cleaning of noisy spectra; predictive modeling of biomarkers; meta analysis; and causality assessment. To enhance our understanding, systems approaches will be considered for pathways and structural modelling of biological networks. The major challenge in the joint analysis of omics datasets will be to develop methods that deal with the high dimensionality, noisy spectral data, heterogeneity, and structure of these datasets.
To perform these tasks successfully we bring together established EU academic and industrial researchers in metabolomics, glycomics, biostatistics, bioinformatics, scientific computing and epidemiology, with complementary expertise. A key feature of our project is the validation of novel methodology by performing a proof of principle (Metabolic Health) . Special effort will be made for rapid uptake of methods by communication with associated consortia and development of user-friendly software.back
Glycosylation is a post-translational modification that enriches protein complexity and function. Dysregulation of glycosylation is associated with a wide range of diseases, including cancer, diabetes, as well as congenital, cardiovascular, immunological and infectious disorders. A number of studies identified potentially important glycan disease biomarkers. With regard to biotechnology, proper glycosylation of biologicals is important, as deviations in glycosylation are known to be associated with adverse drug reactions and reduced therapeutic efficacy. However, glycomics is significantly lagging behind genomics and proteomics, mainly due to the absence of high-throughput analytical methods which can reliably quantify a multitude of glycan structures in complex biological samples.
We are confident that by coordinated efforts of leading European scientists in glycan analysis using HPLC, MS and CGE-LIF technologies this project will make a decisive step forward by developing real high-throughput tools for glycosylation analysis. By teaming up with leading European researchers in the field of genome wide association studies this project will perform validation of all methods on extremely well characterized set of samples resulting from the FP6 EuroSpan project. The addition of the newly generated glycome data to the pre-existing information about these individuals will enable development of methods for the systems biology approach analysis of the glycome which will integrate glycomic, genomic and environmental data about thousands of individuals. The same methods will also be adapted for quality control and monitoring in the production of biopharmaceuticals.
Strong participation of SMEs in the project and close contacts with large industrial partners will ensure that research accomplishments achieved by collaboration between academic and industrial scientists are swiftly transformed into innovative products and services for the benefit of European industry.back
Glycosylation patterns on glycoproteins and glycolipids are involved in the regulation of inter- and intracellular recognition events and alteration of such glycosylation has been observed in many diseases, notably in a variety of cancers. We propose that a systematic, large scale investigation in this area will provide a rich spectrum of novel and structurally diverse carbohydrate-based highly specific biomarkers. The aim of this project will be to address current bottlenecks in analytical techniques by developing an integrated multidisciplinary approach to glycobiomarker screening and analysis based on current state-of-the-art. We will bring together a number of complementary screening techniques developed in the individual partner laboratories, notably high-throughput LC-ms analysis of carbohydrates, lectins and carbohydrate arrays, to develop an overall workflow for the multiplex analysis of glycobiomarkers. Such carbohydrate-targeted methods will be combined with RNA/DNA and analysis (combining high throughput glycomics with genomics). It will be important to test the workflow against serum and tissue samples of healthy volunteer/cancer patients. In addition, we envisage that the project will generate new analytical tools that can be used in routine analysis of glycobiomarkers in the clinic, including diagnostic imaging. Some of the tools developed in this programme (lectins conjugated to nonoparticles) should also be useful for new quantitative imaging biomarkers for monitoring therapeutic effects and safety in cancer. The involvement of three SME partners will ensure that the technology is compatible with commercial applications.back
FP7 Project “EuroGlycoArrays - Development of Carbohydrate Array Technologies to Systematically Explore the Functional Role of Glycans in Healthy and Diseased States”
The EuroGlycoArrays project, launched on 01 September 2008, has been granted a 4 million EURO award by the EC to set up a Marie Curie Initial Training Network as part of the FP7 People Programme.
This grant will fund four years of research and training into the development of carbohydrate arrays as highly innovative tools to map out carbohydrate-protein interactions in cells or tissues.
The large-scale project is being coordinated by the University of Manchester, UK, and will be delivered by a consortium of 16 industrial and academic partners.back
Project of the Croatian Ministry of Science “Glycoproteomics of stress and stress-associated disease”
Glycosylation is the most complex posttranslational modification that was apparently crucial for the development of multicellular life. Almost all proteins that evolved after the appearance of multicellular organisms are glycosylated and glycans represent significant part of their molecular structure. However, due to high complexity of glycan structures, the level of knowledge about glycans lags significantly behind the level of knowledge about proteins and DNA. Since a glycoprotein interacts with other molecules as an integral molecule where biosynthetic origin of its individual parts is not relevant, the lack of knowledge about glycan structures is a large obstacle to the understanding of biological processes. Molecules in which the role of glycan was studied in detail clearly demonstrate that in addition to structural roles, glycans frequently have regulatory roles, and that they modulate many physiological and pathophysiological functions.
Stress response is very complex process through which our organism prepares for treats (real or imagined)in the environment. Excessive stress is associated with the appearance and development of numerous diseases. Published data and our previous results indicate that changes of glycosylation are involved in the molecular mechanisms of the stress response. In many stress-related diseases, specific changes of glycosylation have been demonstrated, but it is mostly unknown whether these changes are just a reflection of changed cellular metabolism, or some of these changes also have a role in the etiology of a disease. The aim of this project is to study changes in protein glycosylation, the activity and expression of their lectin receptors, and the expression of genes responsible for glycan synthesis in different pathobiochemical processes and to determine to what extent these changes affect their appearance and course. Genetic polymorphisms of some key glycosyltransferases will be studied and correlated with stress-associated diseases. Tests will be conducted on patients’ blood samples, in animal models of stress and inin vitro models. In stress the line between adaptation and mal-adaptation is rather thin, and it seems that glycosylation plays an important role in crossing that line. Through suggested multidisciplinary research plan, we expect to partially enlighten these very complex processes and discover potential targets for the development of specific drugs that could alleviate adverse effects of stress.back