Objective
Cerebral small vessel disease (SVD) is the leading cause of vascular dementia, plays a significant role in Alzheimer's disease and increases stroke risk, highlighting its critical impact on our ageing population. Endothelial cell dysfunction precedes other pathologies in both human SVD and preclinical models, where a causative deletion mutation and a single nucleotide polymorphism in the phospholipid flippase ATP11B were identified. However, the mechanism of action of ATP11B in SVD remains unclear.
ATP11B is thought to mediate the translocation of phospholipids phosphatidylserine (PS) and phosphatidylethanolamine (PE) from the outer to the inner leaflet of plasmalemmal and intracellular vesicular organelle membranes. Both PS/PE contribute to membrane curvature and are essential for function of vesicular organelles. Single-nucleus transcriptome data from human SVD donors suggests involvement of lysosomal/autophagosomal pathways in SVD-affected endothelial cells, while loss of ATP11B disrupts membrane integrity, indicating that lipid changes drive SVD pathology.
In PHOS-SVD, I hypothesize that loss of ATP11B alters the normal PS/PE lipid signature of endothelial cell membranes, altering lysosomal/autophagosomal function, promoting endothelial cell dysfunction and SVD pathology. Here, I will address 3 objectives in the Atp11bKO rat SVD model, with subsequent validation in human SVD tissue: 1) describe intracellular vesicular organelle function in endothelial cells in SVD, 2) determine PS/PE distribution in endothelial membranes and their action on intracellular vesicular organelle function and 3) examine if manipulation of lysosomal function and autophagy ameliorates endothelial dysfunction.
PHOS-SVD interdisciplinary approach, integrating chemistry, super-resolution imaging and optogenetics, will advance our understanding on lipid membrane signature and its impact on SVD pathology. PHOS-SVD outcomes will help to develop future therapeutics to alleviate SVD burden.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques.
- medical and health sciencesbasic medicineneurologydementiaalzheimer
- natural sciencesphysical sciencesopticsmicroscopysuper resolution microscopy
- natural sciencesbiological sciencesgeneticsmutation
- medical and health sciencesbasic medicinepathology
- medical and health sciencesbasic medicineneurologystroke
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Programme(s)
- HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA) Main Programme
Funding Scheme
HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European FellowshipsCoordinator
EH8 9YL Edinburgh
United Kingdom