Project Reference: TRG27-CNS-AG1

Project title: Decoding Genetic Risk in Cerebral Small Vessel Disease

Project outline

Cerebral small vessel disease (cSVD) is a major cause of stroke and vascular cognitive impairment, yet individuals with apparently similar risk factors can develop markedly different levels of disease. The biological mechanisms underlying this variation in susceptibility are poorly understood. This project will investigate how an individual's genetic background influences the function of cells forming the brain's small blood vessels.

The project will use a unique collection of more than 20 patient-derived fibroblast lines from individuals with sporadic cSVD, together with available clinical information. The student will use genetic profiling and established polygenic risk scores to investigate whether genetic susceptibility is associated with disease severity and identify individuals representing contrasting genetic and clinical phenotypes. Selected patient lines will be reprogrammed into induced pluripotent stem cells (iPSCs), building on two iPSC lines already generated in our laboratory.

The student will differentiate patient-derived iPSCs into relevant vascular cell types, including brain endothelial and mural cells, and investigate how genetic susceptibility is reflected in cellular phenotypes. Functional studies will assess properties relevant to cerebrovascular disease, including blood–brain barrier integrity, vascular cell function, inflammatory responses and interactions between vascular cell types. Molecular profiling will then be used to identify biological pathways associated with increased susceptibility or relative resilience to disease.

Finally, candidate mechanisms will be investigated using genetic or pharmacological approaches to determine whether alterations in key pathways contribute causally to vascular dysfunction.

The project will integrate human genetics, stem cell biology, vascular biology and molecular approaches to establish a mechanistic link between genetic susceptibility and cerebrovascular dysfunction.

Principal Supervisor

Dr Alessandra Granata

Email address: ag686@cam.ac.uk

Department / Partner Institute: Clinical Neurosciences

Website: https://www.cardiovascular.cam.ac.uk/directory/agranata

BBSRC strategic theme

Bioscience for an integrated understanding of health