Project description
Understanding cerebral small vessel disease mechanisms
Cerebral small vessel disease (SVD) is a major cause of vascular dementia, increasing stroke risk and worsening Alzheimer's. Endothelial cell dysfunction is an early event in SVD and is linked to reduction in the ATP11 enzyme. Supported by the Marie Skłodowska-Curie Actions programme, the PHOS-SVD project will address three objectives using the Atp11bKO rat model, with validation in human SVD tissue. The project will explore the function of intracellular vesicular organelles in endothelial cells, examine PS/PE distribution in endothelial membranes, and assess how manipulating lysosomal function and autophagy affects endothelial dysfunction. The findings aim to inform future therapeutic strategies to alleviate the burden of SVD.
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. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- medical and health sciences basic medicine neurology neurodegenerative diseases dementia alzheimer
- natural sciences physical sciences optics microscopy super resolution microscopy
- natural sciences biological sciences genetics RNA transcriptomes
- natural sciences biological sciences genetics mutation
- medical and health sciences basic medicine pathology
- natural sciences biological sciences genetics nucleotides
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Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
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Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA)
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Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European Fellowships
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(opens in new window) HORIZON-MSCA-2024-PF-01
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EH8 9YL Edinburgh
United Kingdom
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