Project No. 2413

STANDARD PROJECT

Primary Supervisor

Prof Katrin Deinhardt – University of Southampton

Co-Supervisor(s)

Prof Majid Hafezparast – University of Sussex

Dr Yihua Wang- University of Southampton

Summary

Neuronal activity within the brain is tightly regulated to enable our daily lives.

Neuronal activity within the brain is tightly regulated to enable our daily lives. A multitude of cellular mechanisms ensure the dynamic adjustment in response to external stimuli or internal changes. We recently found that a dioxygenase that preferentially targets ankyrin-repeat domains, FIH, is expressed in neurons. Many protein that organise neuronal excitability harbour ankyrin repeat domains, making them candidate substrates for asparagine (Asn) hydroxylation by FIH. Indeed, we showed that inhibition of FIH increases neuronal firing frequency. This project will investigate under which conditions FIH is active and hydroxylating its targets in neurons.

The project will make use of a reporter system that informs on FIH activity. This reporter will be expressed in neurons to understand at what stages of a neuron’s life course FIH-mediated hydroxylation occurs. Specifically, it will address (1) whether, and a which stages, FIH is active during neuronal development, (2) how changes in the activity of established neuronal networks relate to FIH activity and whether there is a feedback mechanism, and (3) whether FIH responds to age-related insults to established neuronal networks. The use of this bioluminescence reporter system will be complemented with high resolution live cell imaging to monitor neuronal network activity, and pharmaceutical and molecular approaches to manipulate FIH and monitor the outcome of that manipulation on neuronal network establishement and homeostasis.

This will enhance or understanding of an under-investigated stable post-translational protein modification on brain activity across the life course.

A background in cell biology and keen interest in neurobiology will be helpful.