Redox Biology Laboratory

Lab head: Dr Paul Witting
Location: Blackburn Building, Camperdown Campus

Protein modifications that potentially underlie the severity of acute myocardial infarct in hearts from diabetic rats. In addition, we have an established interest in monitoring oxidative stress in disease states including atherosclerosis, acute renal failure and cerebral ischemia injury (stroke).

Funding: ARC; National Heart Foundation; Diabetes Australia
Research approach equipment: Analytical Biochemistry: using analytical techniques such as liquid chromatography and liquid chromatography coupled with mass spectrometry, the redox biology lab assesses the mechanism of acute pathological processes. Molecular biology: we use quantitative gene analysis techniques to assess cellular and tissue response to experimental ischaemia reperfusion injury as a model for stroke and heart attack.

Exploring a role for the heme protein neuroglobin in protecting neuronal cells from acute injury

Primary supervisor: Paul Witting

Aims and background – Numerous important molecular processes within cells require the formation of
large molecular machines that are comprised of highly organised functional protein sub-units arranged
through specific protein-protein interactions. Functional protein–protein interactions form the central core
of living cells and perturbations in these interactions can promote cellular dysfunction that impacts on
metabolic networks central to cell survival.

Brain cells including neurons and astrocytes contain the haem protein neuroglobin, which was
discovered in 2003, but whose biological function is not well known. Identifying a role for
neuroglobin in neuronal cell biology is a focus for laboratories worldwide. In recent studies, the Redox Biology Group
reported that neuroglobin protects cultured neurons from experimental hypoxia by sustaining
mitochondrial ATP production and stabilising metal ion homeostasis.

This work also implicated neuroglobin in the activation of a cell survival transduction cascade involving
phosphoinositide 3-kinase (PI3K) activation that yields phosphorylated proteins central to maintaining
cell viability. It is important to know how neuroglobin interacts with other cellular proteins such
as PI3K as this may underpin the role for neuroglobin in cellular signaling in response to a changing
cell environment. Identifying lead drugs that mimic or bolster neuroglobin activity within neuronal cells
will provide novel approaches to inhibit cerebral disorders including acute injury or neurodegenerative
disease. This proposal thus falls into the ARC research goal of ageing well and ageing productively.
The central hypothesis is that neuroglobin protects neuronal cells from oxidative injury via a mechanism
that involves binding of oxygen and activation of the pro-survival PI3K pathway that together enhance
mitochondrial function and cell viability.

The goal is to identify neuroglobin’s biological functions and reveal the fundamental protein-protein
interactions that are central to these functions.

To achieve this goal the study aims to:
(1) Ascertain whether oxygen binding to neuroglobin is essential to its ability to protect neurons from
oxidative insult;
(2) Characterise neuroglobin’s mechanism of action by linking it to preservation of mitochondrial
function and maintenance of cell energetics;
(3) Characterise post-translation modifications that are fundamental to neuroglobin function; and
(4) Test a series of lead drugs for their ability to confer neuro-protection by increasing neuroglobin
expression in neurons.

Discipline: Pathology
Co-supervisors: Simon Myers
Keywords: Biological and Medicinal Chemistry, Neurobiology, protein structure/function