Research project P5/25 (Research action P5)
The general goal of this research project is to get a full understanding of the function of genes through the in depth analysis of several pathological states either in human beings or in animal models. This goal will be reached by combining the expertise of teams from several Belgian and foreign universities in a multidisciplinary approach involving classical and reverse genetics, molecular biology, cell biology, biochemistry, physiology, pathology etc... Ultimately, this knowledge will also lead to better diagnostic and therapeutic possibilities.
This network represents a re-modeled version of part of network P4/17, working on a similar broad theme and headed by the same two principal partners (CME-KULeuven and ICP-UCL). Our proposal to re-conduct a somewhat modified version of this network is based on the success of our previous network in terms of scientific achievements and ability to perform collaborative research, as stressed by the panel of foreign experts who evaluated it. The re-modeling is also inspired by the suggestions made by this panel of experts.
The work is distributed in 9 different work packages (WP), each of which is taken care of by two or several partners of the network. All these work packages are based on important findings made recently by partners of the network. The diversity of the themes may be somewhat surprising, but we feel that this is an asset, since it will permit the development of new (i.e. that are not yet programmed at this stage), fruitful collaborations between members of the network in the course of the 5-year term of the programme. This goal will be reached by increasing the scientific exchanges between members of the network through regular meetings, circulation of an electronic newsletter and organisation of seminars.
Five work packages (WP) will be devoted to METABOLIC DISORDERS. A first one (WP1) will develop transgenic models to analyse and understand the role of two candidate genes (one of which is a phosphatidylinositol-5-phosphatase) in the molecular pathogenesis of type II diabetes mellitus. WP2 is devoted to the study of the role of a newly identified enzyme, fructosamine-3-kinase, in a putative deglycation pathway. The study of enzymatic deficiencies in the pathway of purine synthesis (adenylosuccinate lyase deficiency) and of L-serine synthesis, all of which result in profound mental retardation, is the subject of WP3. Congenital disorders of N-glycosylation, which lead to multisystemic diseases, often with CNS involvement, are the subject of WP4 whereas WP5 focuses on the further characterisation, and the search of protein ligands, of CFTR, the protein mutated in cystic fibrosis.
In the context of MALFORMATIONS, WP6 aims at identifying and characterising genes playing an important role in cardiac morphogenesis, vasculogenesis and angiogenesis by studying inherited human cardiac and vascular anomalies. The aim of WP7 is the structural and functional genomic analysis of a novel, evolutionary conserved imprinted domain (HSA14q, MMU12q, OAR18q) that is involved in the determination of a complex non-mendelian inheritance pattern described in sheep (polar overdominance), as well as in developmental anomalies associated with uniparental disomies in man and mice.
TUMORIGENESIS is the subject of 3 work packages. WP8, devoted to the molecular aspects of tumorigenesis in neurofibromatosis type 1, focuses on the molecular changes in Schwann cells derived from neurofibromas and malignant peripheral nerve sheath tumors from individuals with neurofibroma-tosis type 1. WP9 aims at the identification of novel genes involved in leukemogenesis and lymphoma-genesis, the analysis of the molecular mechanisms by which these genes participate in tumorigenesis and the evaluation of the diagnostic and prognostic relevance of the genetic aberrations.
