Type 1 diabetes is the most common chronic disease which manifests in early life. Although comprising only 10% of diabetes cases, type 1 diabetes makes up ~40% of the total cost of diabetes to Australia, due to its early life onset and complex clinical management. Type 1 diabetes is an autoimmune disease where the body "turns on itself" and actively destroys the cells which produce the sugar storage hormone insulin. Hence, there is no cure and individuals require life-long insulin administration for survival.

Our team is investigating novel therapies targeting RAGE, an immunoglobulin-like receptor present on many types of immune cells and on endocrine (beta and alpha) cells of the pancreas during the development of T1D. The gene for RAGE is also located in the major region responsible for inherited susceptibility to T1D development. We have previously shown that RAGE inhibition using therapy leads to improvement in beta cell function and health and increases in regulatory T cells (Tregs), decreases in pathogenic CD8+ T cells thereby delaying T1D onset in our preclinical models. We have also shown that having higher levels of certain forms of RAGE helps to protect young people from developing T1D. This PhD is part of a comprehensive program of research in partnership with hospitals, other research teams and industry, integrating both clinical and preclinical studies.  During this PhD project, you will uncover the critical role that RAGE expression on the endocrine beta and alpha cells plays in glucose homeostasis, beta cell damage and susceptibility to diabetes.  

Rationale: Individuals with diabetes and kidney disease make up the greatest proportion of persons requiring a kidney transplant or dialysis in Australia. Susceptibility to kidney disease in diabetes is not well understood, but previous studies have highlighted dysfunction of the power stations of the cells (mitochondria) as a potential mediator. In this project, we aim to better understand how dysfunction in mitochondria can contribute to kidney disease in diabetes. Our previous data has shown that changes in mitochondrial function happen early perhaps even as far back as at the diagnosis of diabetes. We know that a biomarker of mitochondrial function called mtDNA can tell us when this starts and how badly affected the power stations are and this aligns with early changes in kidney function. In this project, we will examine kidney and mitochondrial function in children and adolescents early in the development of diabetes. We will also look at where mtDNA comes from and if it can directly activate the immune system contributing to DKD.  

Hypotheses:  Mitochondrial damage early in diabetes can impact immune cell function contributing to the development of diabetic kidney disease.

Metastasis accounts for over 90% of cancer-related deaths, with triple-negative breast cancer (TNBC) among the most aggressive and metastatic subtypes. Current treatments often fail to eliminate metastatic cells. This project investigates Positive Cofactor 4 (PC4)—a transcriptional regulator overexpressed in TNBC and strongly associated with poor prognosis—as a novel therapeutic target. The team has developed a PC4-targeting PROTAC (Proteolysis Targeting Chimera) designed to degrade PC4, disrupt pro-metastatic signalling (notably TGF-β/SMAD2/3), and selectively kill metastatic cancer cells. This project aims to map PC4-driven pathways, optimise the PROTAC compound, and validate its safety and efficacy in advanced models. The work has potential to yield a first-in-class drug for TNBC and other PC4-driven cancers.

Our laboratory focuses on rare white blood cells called dendritic cells (DC) that initiate and orchestrate immune responses. They are critical for the generation of protective immunity against infections and cancer but also drive deleterious immune responses that cause autoimmune disease and allergy. Understanding DC biology in humans has enormous potential to develop new therapeutics and improve outcomes for millions of patients afflicted by these diseases.

This project will unravel the mechanisms by which human dendritic cells promote immune responses against cancer and how tumour cells manipulate dendritic cells to subvert immune responses. You will utilise cutting-edge techniques, including advanced culture systems, novel human immune cell and tumour models, multidimensional flow cytometry, imaging, CRISPR/Cas9 and bioinformatics. The project will deliver impactful new knowledge that will be applied to develop next-generation cancer immunotherapies.

Cancer dormancy represents a major clinical challenge, as dormant disseminated tumour cells (DTCs) can persist for years after primary treatment and later reactivate to form incurable metastases. Understanding and targeting the biological mechanisms that regulate dormancy, and its reversal is key to preventing metastatic relapse in breast and other cancers.

This project will investigate the molecular pathways that control the induction, maintenance, and escape from dormancy, using established dormancy models, 3D co-culture systems, and in vivo assays. Drawing on recent advances from our lab (https://jeccr.biomedcentral.com/articles/10.1186/s13046-023-02663-8)  and others, we will focus on:

• Cell-intrinsic regulators of dormancy, including cell cycle arrest, quiescence, and autophagy
• Dormancy-inducing signals from the tumour microenvironment, including TGF-β, integrin, BMP and other pathways
• Identification of key molecular switches that trigger reactivation from dormancy (various candidates have been identified)
• Functional validation of candidate genes or druggable targets that sustain latency or drive relapse

We will use advanced techniques such as time-lapse live-cell imaging, transcriptomics, functional genomics (CRISPR screens), and patient-derived organoid models to track and manipulate dormant cell behaviour in real time.

The Alliance for Healthy Ageing (AHA) is supported by a MRFF grant and aims to prevent, delay or reverse frailty in the community. Utilizing a multidisciplinary, integrated, digitally supported, regional consortium the AHA will directly address identified community priorities. This project will build upon the established work of the research and service delivery partners in providing evidence-based, well-evaluated innovations in governance and workforce re-design for vulnerable populations in the rural and remote Western Queensland (Qld) region.

Opportunities exist for a PhD student to work alongside the CHSRI research team to evaluate the implementation of the Alliance for Healthy Ageing in Western Queensland. Supervisors will work with candidates to develop a PhD project that is in line with the candidate’s research interests and fits within scope of other activities.

The student will have the opportunity to gain skills in collecting and analysing quantitative and qualitative data, data management, costing evaluations, consumer and stakeholder engagement, and writing up findings of the project for reports and publications.

Accurate DNA replication is essential for genome integrity, and disruptions in replication fork dynamics contribute to developmental disorders and cancer. This project focuses on the Rearranged L-myc Fusion (RLF) gene, a newly identified regulator of replication fork speed and chromatin architecture. RLF is a zinc-finger transcription factor involved in epigenetic regulation and replication factory organisation. Its fusion with MYCL (RLF-MYCL) in certain cancers suggests a gain-of-function mechanism that drives oncogenesis and disrupts genome stability.

We aim to unravel how RLF and RLF-MYCL fusion regulate DNA replication, cohesin positioning, and 3D genome organisation using innovative tools including DNAscent, a world-first replication mapping assay based on nanopore sequencing, and genome-wide ChIP-seq and Hi-C. This research will provide foundational insights into the role of RLF in normal and cancer cells and guide the development of targeted therapeutics.

Triple-negative breast cancer (TNBC) is a highly aggressive and treatment-resistant subtype of breast cancer with limited targeted therapy options. This project explores a first-in-class CAR-T cell therapy targeting a protein overexpressed in TNBC but minimally expressed in healthy tissues. The project will involve preclinical validation of this therapy in cancer cell lines and patient-derived models, with the potential to combine CAR-T cells with immune checkpoint inhibitors to enhance efficacy. This research contributes to the development of personalised and durable immunotherapy strategies for hard-to-treat cancers.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer and is characterized by a lack of estrogen, progesterone and human epidermal growth factor receptor (EGFR) expression. TNBC is more likely to recur than the other two subtypes and one of the primary challenges to treat TNBC is its intra-tumoral heterogeneity (ITH). Recent evidences have shown that these micro-environmental differences led ITH creates hurdles for effective therapy response. In this project, we discuss the evidence of intratumoral heterogeneity and its impact on the disease progression including sensitivity to different treatment options particularly chemotherapy and immunotherapies (PD1/PDL1 based). In this project, we aim to evaluate this Intra-tumoral heterogeneity of TNBC through next-generation patient-derived 3D tumour organoid and explant models, which can effectively expedite preclinical responses towards immune-antibody-directed therapies.