Investigations

Circuit remodelling following brain trauma represents compensatory changes that may restore lost function. We investigate network remodelling in the visual system of zebrafish as it allows an unbiased systems-based approach to identify the changes and checkpoints that enable compensatory circuit repair. After ablating specific retinal photoreceptors, we will probe changes in network activity and structural remodelling in central visual circuits, as well as investigate the contribution of glial ...

In multiple sclerosis, an “energy crisis”, which entails axonal ATP depletion, contributes to neuronal dysfunction and ensuing neurodegeneration. We have identified dysregulation of the TCA cycle and specifically depletion of its pacemaker enzyme, IDH3, as a critical checkpoint of neuronal energy homeostasis. Targeting IDH3, however, leads only to partial reversal of axonal ATP deficits, pointing to further neuroenergetic checkpoints. We now plan to identify these checkpoints and study their ...

In demyelinating CNS diseases, remyelination is mostly driven by newly differentiating oligodendrocytes (OLs) but often remains insufficient. Our recent work shows that surviving OLs can contribute to myelin repair both in animal models of multiple sclerosis and in patients, although this contribution is often inefficient. We believe that surviving OLs can be recruited to the remyelination process if we target the molecular checkpoints determining their repair capacity in the inflamed CNS. ...

Despite the critical role of microglia in human brain pathologies, the molecular mechanisms that govern the diverse and context-dependent set of phenotypes are poorly understood. This project will introduce a highly versatile human brain organoid-based in vivo platform for investigating human glial cells that operate within a vascularized human brain-like environment. Using this platform, we aim to dissect the molecular networks that control human microglia cell responses during CNS injury in ...

Traumatic brain injuries (TBIs) cause primary tissue damage and activate glial cells to build glial border, thereby delineating the injured brain parenchyma from the healthy surrounding tissue. However, this necessary primary reaction of glial cells often persists. This long-lasting glial activation results in prolonged and exacerbated neuroinflammation that prevents tissue restoration. We propose that a cross-regulatory network between innate immunity pathways and EV cargo defines an important ...

Childhood-onset white matter diseases including multiple sclerosis and monogenetic leukoencephalopathies, are characterized by neuroinflammatory tissue damage. Here, we propose that CD8+ T cell phenotypes within lesions serve as critical immune checkpoints for tissue damage and regeneration. Our objective is to define CD8+ T cell-driven disease and regenerative pathways by utilizing a combination of multifluorescent immunohistochemistry, spatial transcriptomics and multimodal MR imaging in patients ...

In autoantibody-mediated gliopathies, such as Neuromyelitis Optica Spectrum Disorder, pathology often spreads quickly beyond the intital target cell type to affect other glial cells. In this project, we will identify glial-glia interactions that act either as checkpoints of acute pathology spread or as checkpoints of lesion repair. To achieve this, we will use in vivo imaging in animal models, as well as genetic interventions and close correlation with human neuropathology, to study how the ...