Geneva Proteomics Centre: Research activities
Our goal is to develop, improve and automate protein identification and characterization methodologies using 2-DE, mass spectrometry and bioinformatics and to further apply them in the identification of specific disease associated markers and new therapeutic targets.
The diabetes project
Identification of differentially expressed proteins associated with insulin resistance, ß-cell damage and dysfunction and further treatment with an anti-diabetic drug has several long-term objectives. First, it should allow clinicians to apply preventive strategies to patients with a high risk for type II diabetes. Second, the discovery of proteins directly or indirectly involved in the disease conditions should lead to a better understanding of type 2 diabetes pathogenic processes. Third, the establishment of appropriate protein markers should permit the precise classification of type II diabetic patients in subgroups for further more effective targeted therapies. Fourth, it should allow the evaluation of new potential therapies (pharmacoproteomics). Finally, the discovery of any of the above differentially expressed proteins could lead to several other proteins that may be highly important in the comprehension of the disorder. The present proteomics study of liver, liver nuclei, muscle, WAT, BAT and islet samples allowed the detection of 94 significant (p<0.05) differentially expressed polypeptides in obese controls relative to lean. Thirty six of these were significantly (p<0.05) modulated in obese models to the level in lean control after rosiglitazone treatment. Forty three of them were identified by mass spectrometry. However, type 2 diabetes models are heterogeneous as none of them alone reflects the metabolic abnormalities and complications of human diabetes. This emphasizes that the results that have be obtained in the present project still need further confirmation on other models before they can be expended and validated in human. The validation could be also achieved through the modulation of the expression of our DEP in cell or animal models. Measurement of glycemia, lipidemia or insulinemia should allow the evaluation of the effect of the modulation. A protein that is over-expressed can be inhibited by antibodies, antisenses and ribozyme. A protein that is under-expressed can be activated by the administration of the recombinant peptide/protein, gene replacement or increased messenger stability. Alternatively, target modulation and validation can be achieved by the administration of a different compound than rosiglitazone such as PPAR, RXR or PI3kinase activators or repressors. Their effect on the overall protein expression should not only help to validate the targets but also to understand some aspects of the pathogenesis of type II diabetes. For some of the differentially expressed proteins found in the present project, the primary function has a clear relationship with the investigated disease processes (fatty acid and carbohydrate metabolism). For many others, the biological association was much more complex or even impossible to decipher, resulting to questions regarding their potential function. The majority of cellular processes are performed and regulated by multi-protein complexes. Protein-protein interactions are thus highly frequent events. A powerful approach to define the function of a protein of interest is to detect the protein(s) that interact(s) with it. This may lead to the identification of new proteins that share the same pathway and that can help to elucidate the function of the proteins under study. The understanding of the biomolecular pathways and interactions of our differentially expressed proteins will be thus essential in further studies to define their function. In conclusion, proteomic approaches should provide in the near future new clues for the elucidation of the pathogenesis of the various defects involved in type II diabetes and provide major insights into new more effective treatments.
Last modified 18/Sep/2002 by CHH
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