Objective Deposition of the amyloid beta peptide (Abeta) in the brain is critical to the pathogenesis of Alzheimer's Disease (AD). Gamma-secretase is a key enzyme responsible for generating Abeta from its precursor protein.Gamma-secretase has attracted a lot of attention recently because:1) it is a highly unusual protease2) it cleaves many important membrane proteins (Notch, cadherins) and regulates subsequent signalling and3) the enzyme is considered to be a drug target in AD research. Gamma-secretase is the high molecular weight complex composed of at least four essential, integral membrane proteins including presenilin, Nicastrin, Aph-1 and Pen-2.It is particularly important to study the structure-function relationship of gamma-secretase from biological, enzymatical and pathological perspectives. Direct analysis of the structure is difficult because handling such hydrophobic complex in cell and membrane free conditions is extremely problematic. In this project, we plan to take advantage of the camel antibody as a tool for the structural analysis of gamma-secretase. Camel antibodies consist of only heavy chains with highly stable variable regions.The variable region fragment (called nanobody) can be easily expressed as a recombinant protein maintaining specificity and stability. We will immunize camel against the gamma-secretase compex, generate a phage display library of nanobodies, and then screen gamma-secretase binders/inhibitors. Analyses of the obtained inhibitors will provide information about the import ant domains of the gamma-secretase complex. The inhibitors can be applied in a multitude of applications. We will focus on the structural analysis of gamma-secretase, and on cell biological studies. Since these nanobodies can be engineered with modifications that allow them to cross the blood brain barrier, a longer term goal is to use the nanobodies as therapeutics to inhibit gamma-secretase in Alzheimer's Disease. Fields of science natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsproteomicsmedical and health sciencesbasic medicineneurologydementiaalzheimermedical and health sciencesbasic medicinepharmacology and pharmacypharmaceutical drugsnatural sciencesmathematicspure mathematicsmathematical analysisfunctional analysisnatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsenzymes Programme(s) FP6-MOBILITY - Human resources and Mobility in the specific programme for research, technological development and demonstration "Structuring the European Research Area" under the Sixth Framework Programme 2002-2006 Topic(s) MOBILITY-2.3 - Marie Curie Incoming International Fellowships (IIF) Call for proposal FP6-2004-MOBILITY-7 See other projects for this call Funding Scheme IIF - Marie Curie actions-Incoming International Fellowships Coordinator FLANDERS INTERUNIVERSITY INSTITUTE FOR BIOTECHNOLOGY VZW EU contribution No data Address Rijvisschestraat 120 ZWIJNAARDE Belgium See on map Links Website Opens in new window Total cost No data
