Centre for Cell Biology

Principal Advisor: Professor John Fraser (j.fraser@uq.edu.au)

Associate Advisor: TBC

To test the effect of introduction of AI algorithms to help analyse ventilator waveforms and data from the mechanical ventilator. This will include the testing of feasibility and safety, and impact on clinical decision making.

Principal Advisor: Professor Rob Parton (r.parton@imb.uq.edu.au)

Associate Advisor: Dr Ye-Wheen Lim (y.lim@uq.edu.au)

How are nanoparticles transported across different biological barriers from the bloodstream to their target sites? This project will use tumor xenograft models and live imaging in the zebrafish to uncover the trafficking of nanoparticles in a live organism.

Principal Advisor: Associate Professor Nathan Palpant (n.palpant@uq.edu.au)

Associate Advisors: Dr Sonia Shah (sonia.shah@imb.uq.edu.au) and Professor Glenn King (glenn.king@imb.uq.edu.au)

Greater than 90% of drugs fail to advance into clinical approval. Genetic evidence supporting a drug-target-indication can improve the success by greater than 50%. This project aims to make use of consortium-level data resources (UKBiobank, Human Cell Atlas, ENCODE etc) to identify genetic links between genetic targets and phenotypes to help facilitate the translation of drugs from healthy individuals (Phase 1 clinical trial assessing safety) into sick patients (Phase 2 clinical trial assessing efficacy). Finding orthogonal biomarkers of drug action in healthy individuals is critical to de-risk drug dosing when transitioning from Phase 1 to Phase 2 trials. Using ASIC1a as a candidate drug being developed to treat heart attacks, this project will develop a functionally validated computational pipeline to predict orthogonal biomarkers of ASIC1a inhibitor drug action in healthy individuals to help inform dosing in human clinical trials. Computationally predicted biomarkers will be validated using genetic knockout animals and pharmacological inhibitors of ASIC1a. Collectively, this project will help develop proof-of-principle computational pipeline for orthogonal biomarker prediction of drug targets in the human genome.

Principal Advisor: Associate Professor Nathan Palpant (n.palpant@uq.edu.au)

Associate Advisors: Professor Glenn King (glenn.king@imb.uq.edu.au)

The research project will test the hypothesis that acid sensing ion channel 1a (ASIC1a) mechanistically underpins ischemia-induced injury across diverse organs and thus provides both a diagnostic marker and a therapeutic target for tissue ischemia. While ischemic injuries to the heart and brain in the form of heart attack and stroke are the most significant contributors to the global burden of disease, all organs are susceptible to ischemic injury whether in the context of patient care or during the procurement and storage of organs for transplantation. My laboratory aims to accelerate the diagnosis and prevention of organ damage due to tissue ischemia. This project stems from our elucidation of ASIC1a as a novel target for ischemic injuries and our discovery of Hi1a, the most potent known inhibitor of this channel, from venom of an Australian funnel-web spider. In preclinical studies we showed that Hi1a is a safe and potent therapeutic that reduces brain injury after stroke, improves recovery after a heart attack, and enhances the performance of donor hearts procured for transplantation. These remarkable therapeutic properties stem from Hi1a’s ability to protect cells from ischemic injury by inhibiting ASIC1a. Exciting preliminary data demonstrating that Hi1a interacts only with ASIC1a in tissue regions experiencing acute ischemia and not in healthy or the remote zone of injured tissue. This presents a unique opportunity to develop Hi1a as a diagnostic tool (theranostic) to measure the progression of ischemic injuries using clinical imaging methods. This project will develop peptidic ASIC1a inhibitors as a diagnostic marker of tissue ischemia. We will develop radiolabelled peptides that bind to ASIC1a with high affinity  to image the progression of organ ischemia in vivo using positron emission tomography-magnetic resonance imaging (PET-MRI). The project will also determine the temporal-spatial activation of ASIC1a-Hi1a interactions across organ systems in response to acute acidosis. Using a murine model of global hypercapnic acidosis, we will determine ASIC1a-Hi1a interactions at a tissue and sub-cellular level during acute ischemic stress to reveal the broader therapeutic landscape for ASIC1a inhibitors. The over-arching goal of this project is to understand the biology of ASIC1a stress response mechanisms across diverse organ systems. 

Principal Advisor: Dr Brett McKinnon (IMB)

Associate Advisor: A/Prof Emaneual Pelosi (UQ Centre for Clinical Research)

The endometrium is a key organ of the reproductive system. It is a complex biological structure of epithelial glands, vascularised stroma and infiltrating immune cells that require intimate communication for normal function. The endometrium is unique in that it undergoes cyclical shedding and regeneration each month regenerated from the resident mesenchymal stem and epithelial progenitor cells in the basalis layer. The maturation and differentiation of these cells into a fully functional endometrium must be tightly regulated. Variations in this maturation from stem cell to mature cell could lead to aberrant cell subsets that increase disease susceptibility and underpin disease variations.

We propose to apply complex organoid and translation models to study stem cell maturation in the endometrium, identify the relationship between altered maturation and molecular signatures of disease and identify the potential to personalise treatment based on these signatures. We will use a combination of single-cell and spatial multi-omics data to determine gene and protein expression and quantitative microscopy to map endometrial maturation and its relationship to reproductive disease. This project will develop skills in both wet-lab and dry-lab techniques incorporating experimental design, performance and data analysis.

Principal Advisor: Professor John Fraser (j.fraser@uq.edu.au)

Associate Advisors: Dr Jacky Suen (j.suen1@uq.edu.au) and Dr Nchafatso Obonoyo (g.obonyo@uq.edu.au)

To investigate whether endothelial stabilisation and resuscitation in septic shock improves organ function.

Principal Advisor: Dr Benjamin Weger (IMB) 

Associate Advisor: Dr Juergen Goetz (QBI); A/Prof Frederic Gachon (IMB)

Alzheimer’s disease (AD) is a neurodegenerative disorder that affects millions of people worldwide. One of the factors that may contribute to AD development and progression is chronodisruption, which occurs when the circadian clock is misaligned with the environmental light-dark cycle. This can happen due to shift work, aging, or exposure to aberrant light patterns. Chronodisruption can impair cognitive performance, mood, and sleep quality in people with AD. Moreover, it can precede the onset of clinical symptoms by several years. Bright light therapy has been shown to improve some of these aspects in AD patients, suggesting a causal link between light exposure, chronodisruption and AD.

In this project, we will use a mouse model of AD that exhibits early cognitive impairment and expose it to an aberrant light regimen that mimics the disrupted light environment often experienced by people with AD. We will assess the effects of this regimen on circadian rhythms, memory and learning abilities and molecular markers of AD pathology. This project will reveal how aberrant light exposure influences AD progression and provide insights for developing chronotherapeutic strategies that could slow down or prevent AD.

Principal Advisor: Dr Jacky Suen (j.suen1@uq.edu.au)

Associate Advisor: Professor John Fraser (j.fraser@uq.edu.au)

Donor hearts are extremely sensitive to time once extracted from donor, with increasing time directly associated with increased graft dysfunction and patient mortality. The PhD fellow will work with leading clinical scientists in cardiac transplantation to push the boundary of donor heart preservation. Our previous work has extended the allowable storage time from 4 to 8 hours. This PhD will be the first worldwide to examine the feasibility to further extend this beyond 12 hours. This study is funded by an NHMRC Ideas grant.

Principal Advisor: Dr John Kemp (IMB)

Associate Advisor: Dr Anne Lagendijk (IMB); Dr Dylan Bergen (University of Bristol, UK)

Genetic association studies offer a means of identifying drug targets for disease intervention. However, few of the causal genes underlying skeletal disease associations have been identified and functionally validated in vivo. Our team has developed a workflow that integrates genetic association study results, single-cell transcriptomics, and phenotype data from knockout animal models to identify disease-causing genes and predict the cellular context through which they function. Unpublished results from our team suggest that vascular cell-specific genes have underappreciated roles in bone homeostasis. This PhD project aims to better understand how vascular genes contribute to the development of skeletal disease. 

Research objectives: 
(i) To define a single-cell RNA sequencing census of different cell types, present in the bone microenvironment of zebrafish, and contrast the transcriptomic profiles of different bone cells across mice, and humans.
(ii) Investigate whether profiles of different bone cell types are conserved across species, and whether vascular cell types are also enriched for skeletal disease associated genes. 
(iii) Identify candidate vascular cell-specific genes (and drug targets) and validate their predicted roles in skeletal disease using zebrafish knockout models and live imaging to monitor vessel network formation and function.

Principal Advisor: A/Prof Frederic Gachon (IMB)

Associate Advisor: Dr Frederik Steyn (UQ School of Biomedical Sciences)

Associated with obesity and a sedentary lifestyle, T2D affects around 10% of the world’s population, mainly associated with morbid obesity. T2D starts with a pre-diabetic state characterized by an increased blood glucose level caused mainly by insulin resistance. As insulin overproduction occurs over a long period of time, insulin-producing pancreatic beta-cells lose their capacity to produce insulin, defining the beginning of T2D. Associated with obesity, insulin resistance is triggered by inflammation and fibrosis initiated by lipid accumulation. Metabolic diseases, including T2D, are characterized by a strong sex-specific difference of incidence defined by sex-dependent physiology and metabolism. This sex-specific difference is caused, in part, by the dimorphic secretion pattern of growth hormone (GH) between males and females. Interestingly, GH secretion is perturbed during T2D and has been associated with the development of the disease. However, in both human and animal models, changes in GH secretion protects against T2D, even in obese individuals. Therefore, we hypothesize that modulation of GH secretion pattern could be a protective response of the organism to counteract the development of T2D. The goal of this project is to test this hypothesis, opening new avenues for the treatment of T2D using time resolved sex-specific administration of GH.

Principal Advisor: Prof Kate Schroder (IMB)

Associate Advisor: Dr Sabrina Sofia Burgener (IMB); Prof Avril Robertson

Inflammasome inhibitors offer tremendous promise as new disease-modifying therapeutics. Inflammasomes are signalling platforms with caspase-1 (CASP1) protease activity that induce potent inflammatory responses, including pathological inflammation and disease in many human conditions, such as chronic liver disease. Inflammasomes are thus exciting new drug targets, with inhibitors of one inflammasome (the NLRP3 inflammasome) entering Phase 2 clinical trials for the treatment of genetic auto-inflammatory disease and neurodegenerative diseases. Inhibitors that target multiple inflammasomes (e.g. CASP1 inhibitors) are currently under development for treating diseases driven by multiple inflammasomes (e.g. chronic liver disease). But the beneficial functions of these new therapeutics might come at a cost – a “trade-off” – of promoting patient susceptibility to infection. This is because inflammasomes also exert protective functions in host defence against microbes. For example, the NLRP3 inflammasome is essential for host defence against the clinically-important fungus Candida albicans limiting fungal dissemination and reducing disease, while in immunocompromised patients, C. albicans causes severe and life-threatening infections.

This project seeks to understand whether the future clinical use of inflammasome inhibitors for inflammatory disease treatment may come with the therapeutic trade-off of compromised host defence against C. albicans.

Principal Advisor: Professor John Fraser (j.fraser@uq.edu.au)

Associate Advisors: TBC

To study the feasibility, safety, and effectiveness of introduction of various technologies (including VR) and ability of patients to exercise, and impact on patient outcomes.

Principal Advisor: Dr Jacky Suen (j.suen1@uq.edu.au)

Associate Advisor: Professor John Fraser (j.fraser@uq.edu.au) 

Increasing number of patients with critical cardiac-respiratory failure is supported by advanced life support. Yet, certain conditions have failed to see any improvement in patient outcomes. The PhD fellow will work with industry leader to examine and develop the next generation advanced life support. Our previous study demonstrated superiority of pulsatile blood flow in supporting patients with cardiogenic shock. This PhD will focus on further understanding the underlying physiological and biological impact of blood flow pattern.

Principal Advisor: Dr Fleur Garton (IMB)

Associate Advisor: Dr Adam Walker (QBI); Dr Allan McRae (IMB)

Motor neuron disease (MND) is a devastating disease for those affected and their family. It is an adult-onset, neurodegenerative disorder that progressively leads to paralysis and death. For most individuals with MND, diagnosis comes as a surprise, with no family history. The estimated genetic contribution to disease is significant and genome-wide association studies (GWAS) are now identifying these. The causal gene/mechanism is not known and further analyses must be carried out. 

This project aims to identify molecular mechanisms contributing to MND to help support the path to translation. It will harness the in-house, Sporadic ALS Australia Systems Genomics Consortium (SALSA-SGC) platform. The current cohort, N~400 cases and N~200 controls is larger than existing datasets and has a rich set of matched data both genomic and clinical. Samples will be run for ‘omics analyses including DNA methylation and RNA-seq. Profiling expression with genomic and clinical data is expected to help identify lead disease mechanisms. Any new finding can be modelled in-vitro or in-vivo using cell or animal models. There is no effective treatment for MND and this project will help drive progress in unlocking molecular variations that contribute to the disease.

Principal Advisor: Professor Rob Parton (r.parton@imb.uq.edu.au)

Associate Advisor: Dr Harriet Lo (h.lo@imb.uq.edu.au) and Dr Tom Hall (t.hall5@uq.edu.au)

We recently discovered a novel process whereby eukaryotic cells are able to kill invading pathogens using lipid droplets. This project will use cell-based infection models and live imaging in zebrafish to identify and characterise the proteins involved.

Principal Advisor: Dr Melanie White (IMB)

Associate Advisor: Dr Samantha Stehbens (AIBN); Prof Alan Rowan (AIBN)

Despite significant progress by scientists and clinicians, melanoma is often fatal due to rapid spread throughout the body, especially to the brain. The brain is vastly different to other tissues, and melanoma is particularly efficient at travelling to the brain and surviving in the new environment to establish disease there.  Clinically, it is difficult to stop melanoma spreading to the brain and once it is there, it is complicated to treat. This is because melanoma in the brain is distinct due to the differences in the tissue structure and types of cells surrounding the tumour.  This project will seek  to develop novel integrative cancer models including cell biology and quail embryo xenograft models, to understand how melanoma survives in the brain microenvironment. By understanding crosstalk, we aim to identify a novel mechanism to block transmission of signals from the tumour microenvironment- inhibiting melanoma proliferation, survival, and invasion. This project is cross-disciplinary integrating cell biology with neuroscience and vascular biology.

Principal Advisor: Dr Jacky Suen (j.suen1@uq.edu.au)

Associate Advisor: Professor John Fraser (j.fraser@uq.edu.au)

This project focuses on the use of mitochondria transplantation to improve the quality and function of donor heart, in order to reduce the risk of primary graft dysfunction, as well as improving utility of marginal donor heart. Currently up to 80% of hearts were discarded, partly due to existing conditions. This is becoming an increasing problem as Australian faces an aging population. The fellow will work closely with our collaborator at Harvard Medical School and initial funding awarded from the Heart Foundation.

Principal Advisor: Dr Tom Hall (t.hall5@uq.edu.au)

Associate Advisor: Dr Harriet Lo (h.lo@imb.uq.edu.au)

The results of genetic testing in humans are often difficult to interpret. This project will use live imaging and CRISPR/Cas9 technology to introduce human variants into zebrafish and examine the effects on muscle and adipose tissue.

Principal Advisor: Prof David Fairlie (IMB)

Associate Advisor: A/Prof David Vesey (ATH, UQ Faculty of Medicine and Department of Nephrology, Princess Alexandra Hospital); Dr James Lim (IMB)

G protein-coupled receptors (GPCRs) are membrane-spanning proteins expressed on the cell surface and they act as signalling mediators between chemicals and proteins outside cells and signalling networks inside cells, enabling transduction of chemical signals into diverse physiological responses. Some of these receptors are the targets for about a third of all known pharmaceuticals, yet most GPCRs have not yet been sufficiently studied to become validated drug targets. We have previously discovered a number of GPCRs that are important links between extracellular signalling networks and intracellular metabolic signalling networks that drive inflammation and inflammatory diseases. This project will investigate the signalling connections between cellular activation of GPCRs and immunometabolic outputs that drive mouse models of chronic inflammatory/fibrotic disease associated with the liver/kidney. Techniques to be applied include PCR, western blots, cell culture, CRISPR-Cas9, flow cytometry, fluorescence microscopy, ELISA, G protein and b-arrestin signalling, GPCR secondary messenger assays (Ca2+, cAMP, ERK, Rho, arrestins, etc) and administration of experimental drugs to mouse models of chronic disease, measurement of metabolic, inflammatory and disease markers in tissues and cells. The project will be aided by availability of unique small molecule GPCR modulators, developed by chemists in our team, as probes and experimental drugs for various diseases. 

Principal Advisor: Prof Jennifer Stow (IMB)

Associate Advisor: Dr Nicholas Condon (IMB); Prof Halina Rubinsztein-Dunlop (UQ School of Mathematics and Physics)

Epithelial cells and neurons are permanently polarised in order to perform directional transcytosis, endocytosis and secretion of many substances. This polarity is essential for allowing epithelial cells to act as selective barriers and for neurotransmission in neuronal networks. Many other cell types become transiently polarised, for instance while they are migrating, when they reorient to have a front and back. Measuring cell polarity is important for understanding both how cells and tissues normally function and the loss of function associated with genetic diseases, cancer, infection and inflammatory disease. This PhD project will create cellular models for measuring polarity and assessing loss of polarity after gene deletions. We will develop a suite of bifunctional, genetically-encoded biosensors as biological and biophysical detectors to measure polarised membrane domains in living cells. Model epithelial cells and neurons expressing these biosensors will be established as 3D organoids or in migration chambers and used to define polarity and to explore loss of polarity.

Principal Advisor: Prof Rob Parton (IMB)

Associate Advisor: Dr Alan Rowan (AIBN); A/Prof Alpha Yap (IMB)

Caveolae, abundant cell surface organelles, have been extensively linked to chronic disease. Changes in the major proteins of caveolae have been linked to numerous cancers including breast cancer, pancreatic cancer, melanoma, thyroid cancer, gastric cancer, and colorectal cancer. In addition, caveolar proteins are dramatically upregulated in cells treated with chemo-therapeutics and their loss sensitises cells to toxic agents. Understanding the role of caveolae in cancer susceptibility and progression (to invasion and metastasis) requires a complete understanding of how caveolae, both in the cancer cell and the cancer cell environment, respond to intrinsic risk factors and to external stress.

This project will build on our findings that caveolae can sense mechanical and environmental stress. It will test the hypothesis that caveolae can protect cells against mechanical forces by activating signalling pathways from the cell surface to the nucleus and that loss of this pathway can promote DNA damage leading to cancer progression. It will employ novel systems in which defined mechanical stimuli can be combined with genetically-modified cells and state-of-the-art microscopic methods. This will define the role of caveolae in both the host cells, and in the neighbouring cellular environment, and determine the contribution of caveolar dysfunction to cancer progression.

Principal Advisor: Professor John Fraser (j.fraser@uq.edu.au)

Associate Advisor: TBC

To study the quality and quantity of sleep for patients admitted to ICU. Also, to validate various proposed new methodologies to objectively evaluate sleep against current gold standard polysomnography. Finally, to evaluate the effect of an improved ICU bedspace environment on patient outcomes.

Principal Advisor: Prof Matt Sweet (IMB)

Associate Advisor: Prof Michael Yu (AIBN)

Macrophages are key cellular mediators of innate immunity. These danger-sensing cells are present in all tissues of the body, providing frontline defence against infection and initiating, coordinating, and resolving inflammation to maintain homeostasis. Dysregulated macrophage activation drives pathology in numerous inflammation-associated chronic diseases, for example chronic liver disease, inflammatory bowel disease, rheumatoid arthritis, atherosclerosis and cancers. Emerging technologies, including nanoparticle-mediated delivery of mRNAs and small molecules, provide exciting new opportunities to target otherwise "undruggable” intracellular molecules and pathways within macrophages. Such approaches hold great potential for manipulating macrophage functions to suppress inflammation-mediated chronic disease. This project will characterize and target specific pro-inflammatory signalling pathways in macrophages as proof-of-concept for intervention in chronic inflammatory diseases.

Principal Advisor: Prof Alpha Yap (IMB)

Associate Advisor: Dr Julie Davies (Mater, UQ)

The inflammatory bowel diseases, Crohn’s Disease and Ulcerative Colitis, are chronic diseases that display patterns of relapse and remission which contribute significantly to the burden that they carry. A key to reducing this burden, both for patients and the community, lies in being able to prolong how long patients stay in remission from active disease. Common approaches to maintain remission include immunosuppression and cytokine inhibitors, but these carry significant side effects and often eventually fail. In this project, we aim to investigate alternative ways to understand the mechanisms that lead to relapse, as a foundation to design new therapies. Specifically, our recent discoveries indicate that the mechanical properties of the bowel epithelium may play a critical role in relapse. Increased mechanical tension prevents the bowel epithelium from eliminating injured cells, thus increasing their capacity to provoke inflammation and disease relapse. We will pursue this by developing new clinically-applicable diagnostic tools to evaluate tissue mechanics and test how correcting mechanical properties can prevent disease relapse. Our goal is to support remission through approaches that can complement currently-available therapies.

Principal Advisor: Dr Emma Gordon (IMB)

Associate Advisor: Dr Mark Allenby (UQ School of Chemical Engineering)

Blood vessels are comprised of an ordered network of arteries, veins and capillaries, which supply oxygen and nutrients to all tissues of the body. Growth and expansion of the vascular system occurs during embryonic development, or in response to tissue injury or disease in the adult. As a result of their unique functions, vessels are subjected to distinct mechanical stresses that confer physical forces on cells that line the vessel wall, such as fluid shear stress, stretch and stiffness. In diseases of the vasculature, such as aortic and intracranial aneurysms, these physical forces become dysregulated, leading to changes in the shape of the vessel and eventually rupture. Using biofabrication technology and advanced imaging techniques, this project will use 3D printed models of the vasculature to study how changes in vessels occur at the molecular level in response to altered physical forces. These findings will allow us to understand how vessels may be manipulated to develop improved therapeutic strategies to prevent expansion and rupture.

Principal Advisor: Dr Angelo Keramidas (IMB)

Associate Advisor: Prof Irina Vetter (IMB); A/Prof Victor Anggono (QBI)

Genetic variants of ion channels that mediate neuronal electrical communication (such as voltage-gated sodium channels and glutamate-gated synaptic receptors) can cause neurological disorders that include epilepsy, ataxia, neurodevelopmental delay and autism spectrum disorder. Understanding the molecular level deficits of an ion channel caused by a variant is essential to accurate molecular diagnosis and tailoring treatment options that correct variant-specific functional deficits. This personalised approach increases the efficacy of treatment, minimises side effects.

This project focussed on variants of voltage-gated sodium channels that are key generators of neuronal action potentials, and synaptic receptors such as GABA- and glutamate-gated ion channel receptors that mediate neuronal inhibition and excitation, respectively.

The project will combine high-resolution and high-throughput electrophysiology and pharmacology as well as ion channel protein synthesis and forward trafficking to understand the pathology of ion channel variants. Standard and new treatment options will be tested against each variant to optimise treatment that is tailored to each variant.

Together these approaches will enhance our understanding of the structure and function of neuronal ion channels and improve our understanding neurological disease mechanisms and treatments.

This project will involve a close collaboration between two groups across two institutes at UQ (IMB and QBI), offering students the opportunity for cross-disciplinary training in neuroscience research with the potential for therapeutic applications for patients.