Molecular insights into a novel mammalian oxygen-sensing pathway

Summary

Oxygen (O2) is a vital biological resource most prominently known for its role as the final electron acceptor in aerobic respiration and, as such, adequate molecular mechanisms are needed to maintain its homeostasis. One eloquent and efficient way this is achieved is through cellular O2 sensors; enzymes with low affinity for the gas, which enable hypoxic (low oxygen) responses to propagate when O2 concentrations fall below a certain threshold.

Recent work conducted in collaboration with researchers at the University of Oxford and the University of Pisa has identified a novel O2 sensing enzyme in humans called cysteamine dioxygenase, knowledge of which may help us understand how mammalian cells adapt to hypoxia (please refer to https://science.sciencemag.org/content/365/6448/65 for more detail). Information on the system could lead to therapeutic strategies to treat detrimental health conditions where oxygen delivery is impaired, such as cardiovascular disease and cancer.

The advertised doctoral project aims to characterise this interesting enzyme in vitro using a variety of (bio)chemical methods and identify inhibitors to modulate its activity for scientific and medicinal benefit.

A complimentary scholarship for this project may be available through a competitive process.  To find out more, refer to the Faculty of Science Postgraduate Research Excellence Award and contact Dr Mark White.

Supervisor(s)

Dr Mark White, Professor Joel Mackay

Research Location

School of Chemistry

Program Type

PHD

Synopsis

Prospective candidates will learn and implement a number of important and fundamental techniques spanning the interface of biology and chemistry to characterise cysteamine dioxygenase at a molecular level, ultimately aiming to determine its mechanism and facilitate the rational discovery of therapeutic compounds to influence its activity. Specifically the applicant will clone, mutate and produce/purify recombinant cysteamine dioxygenase protein, develop and conduct activity assays to analyse wild type and variant enzyme turnover, help identify and validate new cellular substrates using mass spectrometry, elucidate the molecular structure of cysteamine dioxygenase using X-ray crystallography, and design and synthesize chemical inhibitors to modulate enzyme activity.

While these methodologies form the core of the project, there are opportunities for the candidate to drive the work in to alternative areas of interest after they have established themselves in the laboratory.

Additional Information

Applicants should have an interest and background in biological or chemical sciences including, but not limited to, biochemistry, molecular biology and/or organic chemistry. Previous laboratory experience is a significant advantage. There is scope to collaborate with established research groups at the University of Oxford, UK, as part of the project.

A complimentary scholarship for this project may be available through a competitive process. To find out more, refer to the Faculty of Science Postgraduate Research Excellence Award and contact Dr Mark White.

HDR Inherent Requirements

In addition to the academic requirements set out in the Science Postgraduate Handbook, you may be required to satisfy a number of inherent requirements to complete this degree. Example of inherent requirement may include:

- Confidential disclosure and registration of a disability that may hinder your performance in your degree;
- Confidential disclosure of a pre-existing or current medical condition that may hinder your performance in your degree (e.g. heart disease, pace-maker, significant immune suppression, diabetes, vertigo, etc.);
- Ability to perform independently and/or with minimal supervision;
- Ability to undertake certain physical tasks (e.g. heavy lifting);
- Ability to undertake observatory, sensory and communication tasks;
- Ability to spend time at remote sites (e.g. One Tree Island, Narrabri and Camden);
- Ability to work in confined spaces or at heights;
- Ability to operate heavy machinery (e.g. farming equipment);
- Hold or acquire an Australian driver’s licence;
- Hold a current scuba diving license;
- Hold a current Working with Children Check;
- Meet initial and ongoing immunisation requirements (e.g. Q-Fever, Vaccinia virus, Hepatitis, etc.)

You must consult with your nominated supervisor regarding any identified inherent requirements before completing your application.

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Keywords

Biochemistry, Chemical biology, protein, enzyme, Oxygen, Sensing, hypoxia, peptide, Structural biology, X-ray crystallography

Opportunity ID

The opportunity ID for this research opportunity is: 2662