Project description DEENESFRITPL A chimeric in vivo model for studying Alzheimer's disease Despite extensive research into the pathophysiology of Alzheimer's disease (AD), the underlying molecular and cellular mechanisms remain poorly understood. Therefore, better human-related models are needed that preserve disease genetics and more closely reflect the human brain environment. To address this problem, the EU-funded STEMAD3D project proposes to transplant into mice brain organoids derived from AD patient-induced pluripotent stem cells. This chimeric model will provide a physiological environment for investigating molecular and cellular changes during AD progression and delineating the role of the immune system. The project's findings have the potential to lead to novel therapies against AD. Show the project objective Hide the project objective Objective Alzheimer’s disease (AD) is the most common age-related neurodegenerative disease. Despite the significant progress made towards unpacking the pathomechanisms of AD, the molecular and cellular mechanisms underlying AD pathogenesis remain poorly understood. Previous studies mainly relied on animal models that do not capture human-specific biology, monolayer neural cultures that do not capture pathological hallmarks of the disease, and post-mortem tissues that only capture disease end-stage. There is thus a pressing need for new complementary approaches that preserve the disease genetics, mimic disease pathology, and more closely reflect human brain environment. I have developed a chimeric system for transplantation of Induced Pluripotent Stem Cells (iPSC)-derived brain organoids into the mouse brain, providing a powerful platform to study AD under a physiological environment. This project aims to understand the molecular and cellular aberrations underlying AD pathogenesis. I propose to achieve this goal via a novel combination of a chimeric model, iPSC-based patient-specific brain organoids, transcriptomics, epigenetics, and genetic editing approaches. We will determine the disease-associated progressive changes at the transcriptome level, examine the cellular aberrations both in vitro and within the in vivo brain environment, and identify molecular regulators that underlie disease deficits and might enhance susceptibility to AD manifestation. Next, we will define perturbations in the epigenetic landscape associated with AD. Finally, this project seeks to extend towards identifying critical mechanisms that govern the interplay between neurons and the immune system in AD. I anticipate that this research will uncover novel molecular, cellular, and functional mechanisms that govern AD pathology, and may provide a basis for developing future therapeutic strategies. Fields of science medical and health sciencesbasic medicineneurologydementiaalzheimermedical and health sciencesbasic medicineimmunologymedical and health sciencesmedical biotechnologycells technologiesstem cellsmedical and health sciencesbasic medicinepathologynatural sciencesbiological sciencesgeneticsepigenetics Programme(s) H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme Topic(s) ERC-2020-STG - ERC STARTING GRANTS Call for proposal ERC-2020-STG See other projects for this call Funding Scheme ERC-STG - Starting Grant Coordinator THE HEBREW UNIVERSITY OF JERUSALEM Net EU contribution € 1 666 957,00 Address Edmond j safra campus givat ram 91904 Jerusalem Israel See on map Activity type 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 Beneficiaries (1) Sort alphabetically Sort by Net EU contribution Expand all Collapse all THE HEBREW UNIVERSITY OF JERUSALEM Israel Net EU contribution € 1 666 957,00 Address Edmond j safra campus givat ram 91904 Jerusalem See on map Activity type 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
