Elucidating hypoxia signalling pathways in vascular cognitive impairment pathogenesis

This post represents an exciting opportunity for an individual to undertake a PhD elucidating hypoxia signalling pathways in vascular cognitive impairment (VCI) pathogenesis. VCI arises from cardiovascular risk factors. It is thought that reduced blood supply to the brain initiates early endothelial responses that eventually cause oxidative stress, inflammation, and cell death. The brain has an endogenous protective system to cope with reduced blood flow and oxygen -- the hypoxia inducible factor (HIF) pathway. HIF, a master regulator of hypoxic responses in the body, induces several mechanistic pathways have protective roles in cardiovascular diseases. Similar mechanisms likely impact cerebrovascular diseases. Our pilot studies showed FG4592 (Roxadustat) (a clinically approved HIF activator) was able to induce HIF expression in primary rat cortical neurons and protect them from ischaemic injury. The aim of this project is to extend our understanding of the mechanisms by which HIF is protective, and to apply this knowledge towards understanding VCI pathogenesis. We will firstly characterize mechanisms of HIF protection via FG4592 in primary mouse neurons, astrocytes, and microglia, as well as a tri-cellular culture. Subsequently, we will evaluate the effects of FG4592 in a mouse model that recapitulates features of VCI. The knowledge obtained will be used to understand HIF mechanisms relevant to VCI pathogenesis and will further validate the translation of an early pharmacological treatment. The ideal candidate should have a solid background in Neuroscience, Pharmacology, Cell biology, or Biochemistry with strong multidisciplinary interests. The student must be educated to at least a bachelor’s level with a 2:1 classification with evidence of 1st class work. Students with additional experience, for example in the form of a master’s degree, peer-reviewed publications are very much encouraged to apply.