Hypoxia in neurodegenerative diseases: Targets for new therapeutic strategies

Research aims and research hypothesis
The incidence of Parkinson’s and Alzheimer’s disease increases with age, posing serious health concerns. Hypoxia contributes to rapid neurodegenerative decline and impacts on disease progression. Whilst mechanisms exist to allow hypoxic cells to adapt to intermittent low-oxygen environments, hypoxia ultimately causes sustained neuronal damage leading to neurodegeneration. Bioreductive prodrugs (i.e. prodrugs that are activated only under hypoxic-like states) provide a means of imaging the hypoxic-derived state of cell populations and/or initiate cellular adaptation to restore cellular functionality. Our aims are to:
1. evaluate whether novel bioreductive agents reduce the impact of hypoxic states on neuronal cells;
2. use novel bioreductive agents to indirectly image key adaptations within cell populations that contain altered levels of hypoxia derived mediators;
3. evaluate the restoration of cellular functionality.

Methodology and Innovations
Methodology: We propose to use novel bioreductive agents to monitor endogenous hypoxia in a model of neurodegeneration linked to mitochondrial dysfunction, leveraging on state-of-the-art molecular biology technologies (including IncuCyte® Live Cell Analysis and gene expression profiling with the NanoString platform).

Research Design
In vitro molecular studies will use the prodrug to evaluate how mitochondrial dysfunction induces endogenous hypoxia. These experiments will:
1. evaluate direct and indirect endogenous hypoxic conditions on mixed three-dimensional populations of neural cells to examine mitochondrial dysfunction and inflammatory responses;
2. determine how novel bioreductive agents alone and in combination with a hypoxic state can mitigate neuronal damage mediated by mitochondria (seahorse technology);
3. determine the influence of hypoxia and novel bioreductive agents on reactive oxygen species and neurokines.

Ambition & Innovation
These studies will provide a comprehensive macromolecular systems biology profile to highlight the application of novel bioreductive agents in a neurodegenerative condition. We aim to extend the use of these compounds designed to be activated in acute or chronic tumour hypoxia to demonstrate their utility as biomarkers and/or treatments in neurodegeneration.

Applications
Applicants must apply using the online form on the University Alliance website at https://unialliance.ac.uk/dta/cofund/how-to-apply-2/. Full details of the programme, eligibility details and a list of available research projects can be seen at https://unialliance.ac.uk/dta/cofund/

The final deadline for application is 12 April 2019.