Mitochondrial defects as a mechanism of cerebral small vessel disease
Supervisors:
Prof Tom Van Agtmael, School of Cardiovascular and Metabolic Health
Prof Kostas Tokatlidis, School of Molecular Biosciences
Summary:
Cerebral small vessel disease is a major cause of vascular dementia and stroke due to brain bleeding. A poor understanding of its underlying mechanisms contributes to the lack of treatments for this disease that occurs in around 50% of people aged 65. We showed that mutations in the extracellular matrix component collagen IV cause genetic forms of cSVD and contributes to cSVD in the general population. Recent genetic and molecular data suggests altered mitochondrial function may be part of the disease process but this remains poorly defined.
Using a combination of cell culture and mouse models, genome editing and a patient cohort this studentship will determine the extent to which collagen IV mutations affect mitochondrial biology in vascular cells, and how mitochondrial defects affect vascular cell functions. Identified mechanisms will then be validated in animal models of small vessel disease and a patient cohort.
This project will increase fundamental insight into extracellular matrix and mitochondrial biology and small vessel disease. It can also inform on potential future therapeutic strategies for which there is an urgent need.