Understanding mechanisms of cytokine receptor signalling

About this Project

Cytokines are regulatory proteins that play a critical role in many biological settings, particularly those involving haematopoietic cells and immune responses. They have diverse activities and act through specific receptors to regulate many cell types and diverse cellular responses. Understanding the mechanism of cytokine receptor activation and how this gives rise to complex cytokine signalling networks, are questions of fundamental biological significance.

The beta common (Bc) family of cytokines, GM-CSF, IL-3 and IL-5, regulate survival, proliferation, differentiation and activation amongst haematopoietic cells. Their receptors comprise a shared Bc subunit that is the principal signalling subunit and cytokine-specific alpha subunits that are critical for cytokine recognition. Our group is interested in understanding how complex and cytokine-specific signalling programs arise from this type of shared subunit receptor complex, through structural, molecular and cell biology approaches. Insights into cytokine function are of fundamental interest and have practical implications for the development of selective cytokine agonists that can harness desirable properties, such as expansion of haematopoietic progenitor cells in situations of anaemia, but avoiding toxic side effects from cellular activation.

This project will examine the biological outcomes, signalling properties and mechanism of action, of IL-3 mimetic ligands designed to assemble selectively altered IL-3 receptor complexes. The function of IL-3 mimetics will be assessed using; 1) assays of cell differentiation and function, 2) phosphoprotein screens and immunoblotting to assay signalling pathway activation and, 3) transcriptomic analysis to assess differences in gene expression programs. Assembly of IL-3 mimetic Bc receptor complexes will be assessed using cell-based FRET methods or by biophysical and structural approaches using soluble forms of the IL-3 receptor.

What you’ll do

The primary outcome of this project will be fundamental knowledge about the mechanisms underpinning cytokine-specific signalling amongst the Bc cytokines, using interleukin-3 (IL-3) as a model system. The project will also probe the resilience and plasticity of Bc receptor signalling and the extent to which “normal” signalling outcomes can be maintained when the receptor is activated by synthetic ligands. This will help us to understand the impact on IL-3 function of naturally occurring variants of IL-3 or it’s receptor subunits, differences in IL-3 function across species and mechanisms of action for current or future, anti-IL-3 therapeutics.

The exploration of biased receptor signalling amongst the Bc cytokines, may provide lead molecules for the development of novel IL-3 mimetic ligands with selective activity and potential for therapeutic benefit. For example, the potential for selective activation of IL-3-mediated cell differentiation/maturation, in the absence of IL-3-mediated activation of mature cell inflammatory responses, may have therapeutic utility in the setting of leukaemia.

More broadly, this project will increase our knowledge of cytokine function and receptor signalling mechanisms, key areas of biomedical research. It will also result in high impact publications, provide foundation knowledge for future grant funding applications and will establish approaches for developing biased Bc agonists with translational potential. We are confident of success for this project because it makes use of technologies and methods well established in our lab and will build on our significant preliminary work.

Where you’ll be based

Centre for Cancer Biology

Professor Lopez is a world authority on the biology of the Bc cytokine family and his lab have contributed much of the basic knowledge for these cytokines while also exploiting this knowledge to support medical applications. He has been collaborating with internationally renowned structural biologist, Prof Michael Parker, for over 20 years to study the assembly and function of receptor complexes for the Bc cytokines

Dr Damon Tumes and Professor Yeesim Khew-Goodall are group leaders at the CCB. They are the other proposed members of the supervisory panel and have extensive research experience and have supervised numerous post graduate students. Financial Support

This project is funded for reasonable research expenses. A fee offset for the standard term of the program is available to Australian and New Zealand citizens, and permanent residents of Australia, including permanent humanitarian visa holders. Additionally, any Australian Aboriginal and/or Torres Strait Islander applicant who holds an offer of admission without a living allowance will be eligible for the Aboriginal Enterprise Research Scholarship. This scholarship is to the value of $52,352 (2025 rate) per annum. Any Aboriginal Enterprise Research Scholarship recipient will also receive a fee waiver. Where an international applicant holds an external scholarship or sponsorship a full or partial fee waiver may apply in some circumstances for exceptional applicants. Other international applicants will be required to pay full tuition fees of approximately $42,000 per annum (2025 rates).

Eligibility and Selection 

This project is open to applications from both Domestic and International applicants.

Applicants must meet the eligibility criteria for entrance into a PhD. Additionally, applicants must meet the project selection criteria:

• Experience with molecular biology techniques such as DNA isolation, cloning and sequencing, PCR methods for cloning and RNA quantitation, agarose electrophoresis, protein electrophoresis by SDS/PAGE and immunoblotting

Applicant who can also demonstrate the following will be highly regarded:

• Experience with standard tissue culture, cell biology and fluorescence imaging techniques, flow cytometry and analysis of primary blood samples and use of HPLC and low pressure chromatography methods for purification and analysis of proteins
• Experience with bioinformatics tools for the analysis of gene expression, sequence and function or the in silico analysis and modelling of molecular structures
• Experience with the expression, purification and analysis of recombinant proteins for structural or functional studies

All applications that meet the eligibility and selection criteria will be considered for this project. A merit selection process will be used to determine the successful candidate.

The successful applicant is expected to study full-time, and to be based at our City West Campus in the heart of Adelaide. Note that international students on a student visa will need to study full-time.

Essential Dates

Applicants are expected to start in a timely fashion upon receipt of an offer. Extended deferral  periods are not available. Applications close on Wednesday 4 December 2024.