Projektbeschreibung
Ein 3D-In-vitro-Modell von Demenz
An frontotemporaler Demenz erkrankte Personen zeigen eine Degenerierung im Frontal- und im Temporallappen des Gehirns, der mit der Bildung von Proteinaggregaten einhergeht. Bisher gab es keine Behandlungsmöglichkeiten. Das EU-finanzierte Projekt FTD-Organoids wird nun aus embryonischen Stammzellen dreidimensionale Hirnorganoidkulturen erstellen, die nun als erstes In-vitro-Gehirnmodell der frontotemporalen Demenz überhaupt zur Verfügung stehen. Das Forschungsteam wird dieses Modell auf zellulärer wie molekularer Ebene charakterisieren und die Mechanismen hinter der Pathophysiologie einer frontotemporalen Demenz untersuchen. Anhand der Projektergebnisse werden sich neue Angriffspunkte für die Entwicklung therapeutischer Interventionen bei frontotemporaler Demenz finden lassen.
Ziel
Frontotemporal dementia (FTD) is the second most common form of dementia. A pathological hallmark is the formation of protein aggregates that consist mainly of Tau or TDP43. Patients suffer from the degeneration of the frontal and temporal lobes with no effective treatments being available. The recent advancement of 3D brain organoid cultures grown from embryonic stem cells offer new possibilities to study disease mechanisms of neurological disorders and help validate therapeutic interventions. I therefore propose to generate the first cerebral organoid models of FTD. The new models will first be thoroughly characterized by immunohistochemical stainings and biochemical analysis. Furthermore, I will determine neuroaxonal degeneration, visualize protein aggregates and their cell-to-cell spreading and analyze the nucleation of the pathological protein conformation. In addition, I will determine if FTD-organoids recapitulate the brain region- and cell type-specific vulnerability that are observed in patients. FTD has also been linked to aberrant phase transition of proteins that can lead to disturbances in proteome and RNA homeostasis. However, molecular mechanisms and consequences of this processes in disease conditions remain largely unknown. I therefore propose to study the dynamics and molecular composition of stress granules, which are functional biomolecular condensates that arise through liquid-liquid phase separation during stress conditions, in FTD cerebral organoids. Disease-associated changes in stress granule dynamics and thus disturbances in RNA metabolism and regulation of neuronal translational might result in the lack of essential neuronal proteins. I will therefore identify and quantify key mRNA and protein components of neuronal stress granules in brain organoids. In summary, this project will provide new mechanistic insights into disease mechanisms of FTD and open new possibilities of therapeutic interventions.
Wissenschaftliches Gebiet
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsproteomics
- medical and health sciencesmedical biotechnologycells technologiesstem cells
- medical and health sciencesbasic medicineneurologydementia
- natural sciencesbiological sciencesgeneticsRNA
- medical and health sciencesbasic medicinephysiologyhomeostasis
Schlüsselbegriffe
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Aufforderung zur Vorschlagseinreichung
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MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Koordinator
1030 Wien
Österreich