Cel "Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are fatal neurodegenerative diseases with overlapping genetics and pathology. The most common known cause is expansion of a GGGGCC repeat in the first intron of the gene C9orf72. I discovered that the repeat region is translated in all three reading frames into aggregating dipeptide-repeat (DPR) proteins despite its intronic localization and lack of an ATG start codon. DPR aggregates outnumber the previously identified TDP-43 inclusions in the hippocampus, cortex and cerebellum. Some patients exclusively show DPR pathology, strongly suggesting DPR production is a key pathomechanism in C9orf72 mutation carriers. However, we know next to nothing about the mechanisms of translation, toxicity, aggregation and clearance of DPR proteins. With this grant I will characterize this unusual pathomechanism in detail.First, I will generate monoclonal antibodies for a comprehensive analysis of all DPR species to determine the best pathological correlate of disease progression. Insights from patients will drive mechanistic studies and will help to identify therapeutic targets within the DPR cascade. Second, I will develop cell culture models to identify the molecular pathways that determine the expression, toxicity and aggregation of DPR proteins. These models will be used to identify drugs that block all steps of the DPR cascade in pilot screens. Third, I will create transgenic mouse models expressing DPR proteins to rigorously validate the DPR hypothesis by comparing pathology and clinical symptoms of transgenic mice and human C9orf72 patients. Finally, these mouse models will be used to test promising compounds identified in cellular models in prevention and treatment trials. Moreover, I will analyse whether passive immunization with the newly developed monoclonal antibodies allows clearance of DPR proteins from the brain as it has been shown for other intracellular aggregating proteins such as a-synuclein." Dziedzina nauki medical and health sciencesbasic medicineimmunologyimmunisationnatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsmedical and health sciencesbasic medicineneurologydementiamedical and health sciencesbasic medicinepathologymedical and health sciencesbasic medicineneurologyamyotrophic lateral sclerosis Program(-y) FP7-IDEAS-ERC - Specific programme: "Ideas" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Temat(-y) ERC-CG-2013-LS5 - ERC Consolidator Grant - Neurosciences and Neural Disorders Zaproszenie do składania wniosków ERC-2013-CoG Zobacz inne projekty w ramach tego zaproszenia System finansowania ERC-CG - ERC Consolidator Grants Instytucja przyjmująca DEUTSCHES ZENTRUM FUR NEURODEGENERATIVE ERKRANKUNGEN EV Wkład UE € 1 991 000,00 Adres VENUSBERG-CAMPUS 1/99 53127 Bonn Niemcy Zobacz na mapie Region Nordrhein-Westfalen Köln Bonn, Kreisfreie Stadt Rodzaj działalności Research Organisations Kontakt administracyjny Katrin Buerger (Dr.) Kierownik naukowy Dieter Johannes Edbauer (Prof.) Linki Kontakt z organizacją Opens in new window Strona internetowa Opens in new window Koszt całkowity Brak danych Beneficjenci (1) Sortuj alfabetycznie Sortuj według wkładu UE Rozwiń wszystko Zwiń wszystko DEUTSCHES ZENTRUM FUR NEURODEGENERATIVE ERKRANKUNGEN EV Niemcy Wkład UE € 1 991 000,00 Adres VENUSBERG-CAMPUS 1/99 53127 Bonn Zobacz na mapie Region Nordrhein-Westfalen Köln Bonn, Kreisfreie Stadt Rodzaj działalności Research Organisations Kontakt administracyjny Katrin Buerger (Dr.) Kierownik naukowy Dieter Johannes Edbauer (Prof.) Linki Kontakt z organizacją Opens in new window Strona internetowa Opens in new window Koszt całkowity Brak danych