FRIMEDBIO-Fri prosj.st. med.,helse,biol

It is increasingly recognized that intracellular protein misfolding and aggregation are common to many disorders, notably associated to neurodegeneration. Many inherited diseases are also caused by the enhanced tendency of mutant proteins to misfold and t o undergo proteasomal degradation or deleterious aggregation. The understanding of the mechanisms regulating protein stability and homeostasis as well as their alterations leading to pathogenic processes are central to the discovery of new therapeutic app roaches. The focus of the project is the investigation of protein-ligand interactions regulating function and stability in a family of enzymes, the aromatic amino acid hydroxylases (AAH), involved in metabolic networks of high relevance in human disease. The project integrates several methods that are central in functional genomics spanning the structural, functional and thermodynamic characterization of the selected enzymes and their ligand complexes, leading to in vivo studies using animal models and th e initiation of clinical trials. This translational project is thus possible via a synergistic scheme that coordinates i) the competence to be managed by the project leaders (high throughput (HTP)-expression and purification, experimental and in silico H TP-screening of stabilizing ligand binding, thermodynamic characterization, protein-membrane and protein-surface interactions, and, notably, development of Caenorhabditis elegans as a model organism for human disease), ii) the activities to be preformed in existing technology platforms (Bioinformatics, Proteomics, Structural biology), and iii) the competence managed by our collaborators (chemical biology, development of stabilized enzyme by directed evolution, genome-wide SiRNA analysis of C. elegans, knock-out and knock-in mice lines related to the AAH). This integrated approach aids to achieve the quality and critical mass in resources and personnel necessary for the success of the project Folding.