Descripción del proyecto
Un modelo tridimensional «in vitro» de la demencia
Los pacientes con demencia frontotemporal (DFT, o FTD por sus siglas en inglés) exhiben degeneración de los lóbulos frontal y temporal del cerebro vinculada con la formación de agregados de proteínas. Actualmente no existen tratamientos para la DFT, por lo que el proyecto FTD-Organoids, financiado con fondos europeos, empleará cultivos de organoides cerebrales tridimensionales desarrollados a partir de células madre embrionarias como el primer modelo cerebral «in vitro» de la DFT. Los investigadores caracterizarán este modelo a nivel molecular y celular y dilucidarán los mecanismos subyacentes a la fisiopatología de la DFT. Los resultados del proyecto podrían permitir identificar nuevas dianas de la DFT para desarrollar intervenciones terapéuticas.
Objetivo
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.
Ámbito científico
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsproteomics
- medical and health sciencesmedical biotechnologycells technologiesstem cells
- medical and health sciencesbasic medicineneurologydementia
- natural sciencesbiological sciencesgeneticsRNA
- medical and health sciencesbasic medicinephysiologyhomeostasis
Palabras clave
Programa(s)
Régimen de financiación
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinador
1030 Wien
Austria