Project description DEENESFRITPL An in vitro 3D model of dementia Patients suffering from frontotemporal dementia (FTD) present with degeneration in the frontal and temporal lobes of the brain associated with the formation of protein aggregates. Given the lack of FTD treatments today, the EU-funded FTD-Organoids project will employ 3D brain organoid cultures grown from embryonic stem cells as the first in vitro cerebral model of FTD. Scientists will characterise this model at the cellular and molecular level and investigate the mechanisms underlying FTD pathophysiology. The project's results have the potential to identify novel FTD targets for the development of therapeutic interventions. Show the project objective Hide the project objective Objective 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. Fields of science natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsproteomicsmedical and health sciencesmedical biotechnologycells technologiesstem cellsmedical and health sciencesbasic medicineneurologydementianatural sciencesbiological sciencesgeneticsRNAmedical and health sciencesbasic medicinephysiologyhomeostasis Keywords Cerebral organoids liquid-liquid phase separation neurodegeneration pathologic protein conformations Programme(s) H2020-EU.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions Main Programme H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility Topic(s) MSCA-IF-2019 - Individual Fellowships Call for proposal H2020-MSCA-IF-2019 See other projects for this call Funding Scheme MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF) Coordinator INSTITUT FUER MOLEKULARE BIOTECHNOLOGIE GMBH Net EU contribution € 174 167,04 Address Dr bohrgasse 3 1030 Wien Austria See on map Region Ostösterreich Wien Wien Activity type Private for-profit entities (excluding Higher or Secondary Education Establishments) Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Other funding € 0,00
