(MRC DTP) Uncovering mechanisms of vascular dementia using patient-specific induced pluripotent stem cell 3D model

The contribution of vascular defects to neural degeneration has been recognised to be one of the key mechanisms underlying a wide range of dementias, including vascular dementia and Alzheimer Disease. However, the cellular and molecular mechanisms underlying the condition are still largely unknown, therefore, no efficient therapy is available. In the central nervous system (CNS), vascular cells and neuronal cells act synergistically to achieve complex regulation of CNS function, forming the neurovascular unit (NVU). Major cell types within the NVU include endothelial cells (ECs), pericytes or vascular smooth muscle cells (VSMCs), astrocytes and neurones. These neurovascular cells are functionally integrated and tightly regulated, providing a promising target for uncovering disease mechanisms for vascular dementia. Meanwhile, genetic cerebral small vessel diseases provide an excellent model for understanding the contribution of vascular factors to the brain cognitive defect. From our previous study on a genetic vascular dementia syndrome, CADASIL (Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), we have established patient specific induced pluripotent stem cell (iPSC) models, and differentiated the iPSCs into all the different neurovascular cell types. The iPSC models are promising models to dissect functional contributions of each cell type within the NVU to the disease pathologies. However, the conventional 2D cell culture is unlikely able to recapitulate the complicated spatial and temporal interactions between the neurovascular cells. Through interdisciplinary collaboration, we have recently developed a more precise NVU model using 3D cell bioprinting technology. The PhD project will be constructing a human NVU using different combinations of neurovascular cells differentiated from patient-specific or disease-specific iPSCs using the 3D bioprinting technology. The 3D human NVU model will be thoroughly interrogated using molecular and cellular tools, in order to identify key factors or pathways that are common vascular factors involved in dementia, and identify biomarkers and drug targets informing future therapy.

Entry requirements:
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.