Brain-damage Response to Environmental Alterations: Targeting Hypoxia with human multicEllular models
ProgettoThe project pioneers the use of advanced human brain organoid models to dissect hypoxia damage across distinct cell types and injury phases. Microglia, the brain’s resident immune cells, play a central role in hypoxia, either exacerbating damage or facilitating recovery, depending on their activation state. To capture the dynamic interplay of microglia with neurons and astroglia, we will develop neuroimmune chimeroids, integrating microglia from genetically diverse donors into brain cortical organoids. These models will provide an unprecedented window into cell-type-specific vulnerability, injury dynamics, and neuroprotective mechanisms.
By simulating both global and focal hypoxia, we will define the molecular and functional architecture of hypoxic damage using single-cell and spatial transcriptomics, metabolomics, and live imaging. We will investigate functional disconnection, a key yet underexplored consequence of hypoxia, in which surviving neurons lose synaptic integration and network activity, leading to impaired signal transmission and maladaptive plasticity. Given the limited efficacy of current neuroprotective strategies, we will systematically evaluate pharmacological compounds and epigenetic modulators to identify phase-specific interventions.
By targeting epigenetic reprogramming, we aim to reverse maladaptive molecular states and unlock novel therapeutic pathways for brain repair.
By integrating human-specific models, neuroimmune interactions, and precision-targeted therapeutic interventions, this project will reshape our understanding of hypoxia-induced brain injury and lay the foundation for transformative, patient-specific treatments.
By simulating both global and focal hypoxia, we will define the molecular and functional architecture of hypoxic damage using single-cell and spatial transcriptomics, metabolomics, and live imaging. We will investigate functional disconnection, a key yet underexplored consequence of hypoxia, in which surviving neurons lose synaptic integration and network activity, leading to impaired signal transmission and maladaptive plasticity. Given the limited efficacy of current neuroprotective strategies, we will systematically evaluate pharmacological compounds and epigenetic modulators to identify phase-specific interventions.
By targeting epigenetic reprogramming, we aim to reverse maladaptive molecular states and unlock novel therapeutic pathways for brain repair.
By integrating human-specific models, neuroimmune interactions, and precision-targeted therapeutic interventions, this project will reshape our understanding of hypoxia-induced brain injury and lay the foundation for transformative, patient-specific treatments.