PROJECT: JTC2022 - Cerebrovascular: TackleCSVD

Cerebral small-vessel disease (CSVD) refers to a spectrum of sporadic or hereditary chronic pathological alterations of cerebral arterioles, capillaries and venules mostly within the white matter, which lead to vessel rarefication, demyelination, blood-brain barrier (BBB) dysfunction, glial activation and axonal loss. CSVD is responsible for ~30% of ischemic strokes and is a common cause of functional disability and cognitive impairment, imposing an enormous socio-economic burden. Thus, there is the urgent need to develop new therapeutic approaches to treat CSVD. While the majority of studies have focused on characterizing the vascular changes occurring in CSVD, the contribution of cells of the neural parenchyma to the disease remain incompletely understood. In this proposal we hypothesize that lysosomal-autophagy impairment centrally contributes to demyelination, glial activation and neuronal loss in CSVD. To work on this hypothesis we propose an innovative approach to understand and define translational pathways for CSVD, by combining expertise and knowledge of 4 research groups, ranging from the fields of neurology, vascular biology, neurovascular biology and lysosomal biology. Research in this proposal combines CSVD patient samples and mouse models, zebrafish models and in vitro and biochemical approaches. This work will provide the much-needed knowledge on the mechanisms underlying CSVD pathophysiology, as well as new opportunities for targeted therapies.