Global Challenges PhD Projects
2023 Project List
Our 2023 cohort will be tackling the global challenges of Chronic Disease and Drug Discovery through a shared approach examining the issue from different angles, and through an individual project. Please note, applications are now closed but please email imb-studentdev@uq.edu.au if a particular project is of great interest.
A new strategy to treat chronic liver disease
Principal Advisor: Dr Frederic Gachon (IMB)
Associate Advisor: Prof Irina Vetter (IMB)
Non-alcoholic fatty liver disease (NAFLD) is a severe health burden which can progress to cirrhosis and hepatocellular carcinoma. Associated with obesity and a sedentary lifestyle, NAFLD affects around 25% of the world’s population and up to 90% of people with morbid obesity. To date, there are no treatment possibilities available for NAFLD and therapeutic strategies are highly sought after. We recently demonstrated that the size of the liver fluctuates over the day. These daily fluctuations are regulated by circadian and feeding rhythms and accompany the daily rhythms of nutrient storage, drug detoxification and ribosome biogenesis. While high amplitude circadian rhythms are associated with a healthy liver, the rhythmicity of liver size and physiology are attenuated in obesity and liver disease. Our preliminary data suggests that the regulation of ion channels play a role in liver size fluctuation and the development of liver fibrosis. This project aims at identifying new small molecules targeting these ion channels to target liver size with the aim to restore normal liver physiology and counteract the development or even cure NAFLD, opening new avenues for treatment and prevention of NAFLD.
Elucidating how inflammasomes drive chronic inflammatory diseases
Principal Advisor: Prof. Kate Schroder (IMB)
Inflammation drives many devastating human diseases for which patients have no disease-modifying drugs. Uncontrolled inflammation drives conditions such as genetic auto-inflammation, inflammatory skin conditions, chronic liver disease and neurodegenerative diseases. The Inflammasome Lab at IMB is defining the molecular and cellular processes of inflammation. We seek to unravel the secrets of inflammasomes – protein complexes at the heart of inflammation and disease – to enable the development of new drugs to treat human diseases. We are a team of award-winning researchers who enjoy a collaborative, fun approach to science. We value team diversity and multidisciplinarity, and provide a supportive lab culture for outstanding mentoring, teaching, learning, and research outcomes. We encourage applications from prospective students that belong to communities that are traditionally underrepresented in science and academia.
This PhD project will be tailored to the specific interests and career goals of the student, within the broad area of defining how inflammasomes drive pathological inflammation in disease. Projects may involve techniques such as molecular cloning, cell culture, basic and advanced microscopy, immunological assays (ELISA, westerns, flow cytometry), cell death assays and/or assessment of mouse disease phenotypes.
Gender matters: Heart disease risk in women
Principal Advisor: Dr Sonia Shah (IMB)
Associate Advisor: Prof Gita Mishra (School of Public Health)
The 2019 Women and Heart Disease forum highlighted clear disparities in CVD outcomes between males and females. The report (Arnott et al 2019 Heart, Lung and Circulation), highlighted a need to increase our understanding of sex-specific pathophysiology driving susceptibility to common diseases, and identification of sex-specific risk factors to improve early detection and prevention of CVD in women. Until recently, sex-specific research was underpowered and most studies on heart disease included a much smaller number of female participants. But this is beginning to change with the availability of large biobank data.
This project will require statistical analysis of very large datasets with health records linked to genomic data to address these gaps in our understanding of heart disease in women. This includes data from the UK Biobank cohort in ~500,000 individuals (54% women) and data from the Australian Women’s Longitudinal Study (led by Prof Gita Mishra), a study looking at the factors contributing to the health and wellbeing of over 57,000 Australian women, and is the largest, longest-running project of its kind ever conducted in Australia.
This project will lead to a better understanding of sex-specific risk factors for CVD, which will inform better CVD prevention strategies in women.
Gut inflammation: model systems and the development of anti-inflammatory drugs
Principal Advisor: Prof. Jennifer Stow (IMB)
Associate Advisor: Dr Thomas Durek (IMB, UQ) and Dr Simon de Veer (IMB, UQ)
Chronic inflammation in the gastrointestinal tract (or gut) is a debilitating condition that underlies major diseases in humans and animals, ranging from allergies to chronic inflammatory bowel disease (IBD), liver disease and cancer. The use of advanced, cutting edge microscopy and 4D (3D over time) cell imaging is a powerful new method for interrogating the changes in epithelial cells and immune cells in the gut wall throughout the stages of inflammation and for identifying molecules that control inflammation. This imaging will make use of innovative systems for visualising and monitoring the gut mucosa by establishing inflammation in perfused tissues, organoids (mini-guts) grown in the laboratory and model organisms. The outcomes will advance our understanding of gut inflammation and reveal specific molecules as potential drug targets.
A powerful use of these models and imaging is to assess the behaviour of anti-inflammatory peptide-based drugs in a gut environment, as a novel strategy for pre-clinical testing of putative drugs. This project will involve collaborative research with the group of Prof David Craik (IMB) who is currently developing novel peptide-based drugs for use in IBD. Unlike most peptides and proteins, these drug leads show high stability in the gut environment – the models and imaging techniques developed in the project will provide new exciting approaches for studying peptide stability, distribution and function. The project will provide translational training and skills in a high-tech, multi-disciplinary environment and can be offered as a fundamental research project and/or a drug-development focussed project. This project is suited to students with a background in either cell biology or peptide chemistry.
Identifying vascular cell types and genes involved in human skeletal disease
Principal Advisor: Dr John Kemp (IMB)
Associate Advisor: Anne Lagendijk (UQ) and 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.
Investigating the molecular basis of motor neurone disease
Principal Advisor: Dr Fleur Garton (IMB)
Associate Advisor: Adam Walker (QBI) and 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.
Mechanically Induced Inflammation and Cell Death
Principal Advisor: Dr Samantha Stehbens (IMB)
Associate Advisor: Prof Irina Vetter (IMB) and Dr Larisa Labzin (IMB)
Cells in living organisms exist in highly crowded 3D environments where they experience mechanical forces from their surroundings. Mechanical forces are important for cells to move and function in normal and diseased contexts. We recently demonstrated that the microtubules form an adaptive feedback mechanism whereby compressive loading of microtubules recruits a protein called CLASP (cytoplasmic linker-associated protein) to dynamically repair damaged microtubules. This reinforces microtubules, allowing them cell to withstand force and coordinate movement. Disruption of the of CLASP-dependent repair of damaged microtubules stalls cell migration, affects organelle integrity, and ultimately results in catastrophic cell rupture. This project will use cell biology with live-cell microscopy to determine if inflammatory pathways are activated in cells unable to protect themselves in physically challenging environments. We hypothesise that targeting the crosstalk between the cell skeleton and the physical environment may facilitate the development of future therapies that tune inflammatory responses in multiple chronic disease settings from cancer, and neuro-inflammation, to osteoarthritis and autoimmune disorders.
Microenvironmental regulation of Melanoma Brain Metastasis
Principal Advisor: Dr Samantha Stehbens (IMB)
Associate Advisor: Dr Melanie White (IMB) and 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.
Role of caveolae in cancer as a chronic disease
Principal Advisor: Prof. Rob Parton (IMB)
Associate Advisor: Alan Rowan (AIBN) and 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.
Understanding and preventing relapse of Inflammatory Bowel Disease.
Principal Advisor: Prof. Alpha Yap (IMB)
Associate Advisor: Jakob Begun (Mater Medical Research Institute)
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.
Unlocking intracellular targets to suppress macrophage-driven inflammation
Principal Advisor: Prof. Matt Sweet (IMB)
Associate Advisor: 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.
The therapeutic potential of the trefoil factor family in chronic gastrointestinal disorders
Primary Advisor: A/Prof. Markus Muttenthaler
Associate Advisor: Prof. Alpha Yap
Inflammatory bowel diseases (IBD) and irritable bowel syndrome (IBS) affect 10–15% of the Western population, having a substantial socio-economic impact on our society. The aetiology of these disorders remains unclear, and treatments focus primarily on symptoms rather than the underlying causes.
Our research group is pursuing innovative therapeutic strategies targeting gastrointestinal wound healing and protection to reduce and prevent such chronic gastrointestinal disorders. This project focuses on the trefoil factor family, an intriguing class of endogenous gut peptides and key regulators for gastrointestinal homeostasis and protection. The project will focus on the chemical synthesis of the individual members and molecular probe and therapeutic lead development to advance our understanding of their mechanism of action and explore the therapeutic potential of these peptides for treating or preventing gastrointestinal disorders.
The candidate should have a degree in chemistry, biochemistry, pharmacology or cell biology, good hands-on laboratory skills, and strong ambition and work ethics. The candidate will be involved in solid phase peptide synthesis, medicinal chemistry, mass spectrometry, structure-activity relationship studies, NMR, cell culture, wound healing assays, gut stability assays, cell signalling and receptor pharmacology.
The physiological role and therapeutic potential of gut peptides modulating appetite
Primary Advisor: A/Prof. Markus Muttenthaler
Associate Advisor: Dr. Sebastian Furness
The advent of highly-processed, calorie-rich foods in combination with increasingly sedentary lifestyles has seen a rapid rise in overweight and obesity. 60–80% of populations in developed countries are overweight or obese, and over three million deaths each year are attributed to a high body mass index. Obesity is also a risk factor for diabetes, hypertension, cardiovascular disease, kidney disease, and most kinds of cancer. This has a clear impact on life expectancy, with predictions that this generation will be the first to have a shorter life expectancy than the last. Despite this enormous socioeconomic impact, treatment options are limited.
Our research groups are interested in the role of the gut peptides GLP-1 and CCK in regulating appetite and satiety. A subset of GLP-1 mimetics are already successful treatments for obesity, however,compliance is low as they are injectables. The project will focus on the development of orally active mimetics. The project will also develop molecular probes to facilitate the study of the GLP1 and CCK1 receptors in the context of appetite regulation across the gut-brain axis.
The candidate should have a degree in chemistry, biochemistry or pharmacology, good hands-on laboratory skills, and a desire to drive the project. The candidate will be involved in solid phase peptide synthesis, medicinal chemistry, mass spectrometry, structure-activity relationship studies, cell culture, gut stability assays, cell signalling and receptor pharmacology.
Variants of neuronal ion channels that give rise to developmental neurological diseases.
Principal Advisor: Dr Angelo Keramidas (IMB) and Prof Irina Vetter (IMB)
Associate Advisor: 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.
Deconstructing the genetic causes of disease to discover new drug targets
Principal Advisor: Assoc Prof. Nathan Palpant (IMB)
Associate Advisor: Andrew Mallett, Sonia Shah, and Mikael Boden (SCMB)
Despite strong vetting for disease activity, only 10% of candidate new drugs in early-stage clinical trials are eventually approved. Previous studies have concluded that pipeline drug targets with human genetic evidence of disease association are twice as likely to lead to approved drugs. This project will take advantage of increasing clinical disease data, rapid growth in GWAS datasets, drug approval databases, and innovative new computational methods developed by our team. The overall goal is to develop unsupervised computational approaches to understand what genetic models and data are most predictive of future drug successes. Underpinning this work, the project will build and implement computational and machine learning methods to dissect the relationships between genome regulation, disease susceptibility, genetic variation, and drug development. The project will not only reveal fundamental insights into genetic control of cell differentiation and function but also facilitate development of powerful unsupervised prediction methods that bridge genetic data with disease susceptibility and drug discovery. Students with background/expertise in computational bioinformatics and machine learning are ideal for this work. Informed by clinical, computational, and cell biological supervisory team, the project will have an opportunity to engage with diverse international companies through internships and collaborations to facilitate co-design of these methods for uptake in industry discovery and prediction pipelines.
Developing mechanism-based treatments for chemotherapy-induced side effects
Principal Advisor: Dr. Hana Starobova (IMB)
Associate Advisor: Prof Irina Vetter (IMB/School of Pharmacy) and Prof Ingrid Winkler (Mater Research/TRI)
More than 60% of patients receiving tubulin targeting chemotherapy develop debilitating side effects, such as peripheral neuropathy, that are often life threatening, decrease the QOL and survival change of cancer patients. Current treatment strategies poorly control those side effects and often cause additional complications, likely due to lack of understanding of the underlying mechanisms. This project investigates the neuroinflammatory mechanisms contributing to development of chemotherapy induced side-effects. Recent research shows that interactions between different cell types lead to release of pro-inflammatory cytokines via inflammasomes in proximity of peripheral nerves driving neuronal sensitisation and damage. The aim of this project is to understand how tubulin targeting agents influence chemotherapy mediated interactions between endothelial cells, immune cells and neurons using immunology techniques, microscopy, in-vitro and in-vivo studies. The findings of this project will contribute to development of effective preventative treatment strategies for chemotherapy-induced side effects.
Developing new drugs targeting acid sensitive channels to treat ischemic heart disease
Principal Advisor: Assoc Prof. Nathan Palpant (IMB)
Associate Advisor: Jennifer Stow and Brett Collins
This project focuses on strategies to prevent organ damage associated with ischemic injuries of the heart. There are no drugs that prevent organ damage caused by these injuries, which ultimately leads to chronic heart failure, making ischemic heart disease the leading cause of death worldwide. Globally, 1 in 5 people develop heart failure, with annual healthcare costs of $108 B. Our team has discovered a new class of molecules, acid sensitive ion channels, that mediate cell death responses in the heart during ischemic injuries like heart attacks. This project will study the function of acid sensing channels using cell and genetic approaches. We will use innovative new drug discovery platforms to find new peptides and small molecules that inhibit acid channel activity. Finally, the project will use disease modelling in stem cells and animals to evaluate the implications of manipulating these channels using genetic or pharmacological approaches to study the implications in models of myocardial infarction. The candidate will benefit from background/expertise in cell biology and biochemistry. Collectively, this project will deliver new insights, tools, and molecules that underpin a key area of unmet clinical need in cardiovascular disease. The project will be supervised by experts in drug discovery, cell biology, and cardiovascular biology and includes opportunities for internships with industry partners such as Infensa Bioscience, a new spinout company from IMB developing cardiovascular therapeutics for heart disease.
Development of PET Imaging Tracers for Bacterial Infections
Principal Advisor: Assoc Prof Mark Blaskovich (IMB)
Associate Advisor: Dr Karine Mardon (NIF Facility Fellow and Molecular Imaging Facility Manager, CAI) and Dr Christoph Barkhausen (NIF Radiochemistry Fellow, CAI)
Bacterial infections, particularly those caused by resistant organisms, are a global threat to human health. While much attention is focused on developing better therapies, there is an urgent need to improve diagnosis in order to more rapidly select and monitor optimal treatment, reducing unnecessary use of ineffective antibiotics and improving therapeutic outcomes. In many cases infections are suspected to be present but their location cannot be determined, reducing the ability to prescribe the best therapy. Chronic infections, such as infective endocarditis and prosthetic joint infections have high mortality and morbidity yet are particularly difficult to accurately diagnose without invasive techniques. There are no clinically-used whole body imaging techniques that can specifically identify bacterial infections.
We have been modifying antibiotics that specifically bind to the surface of bacteria, attaching fluorescent substituents to create fluorescent tracers that selectively illuminate bacteria. This project will create diagnostic tracers to image bacterial infections by replacing the fluorophore with a chelating substituent that complexes radioactive metals. The goal is a probe that can be injected into patients and used to diagnose the presence and location of bacterial infections by imaging with positron emission tomography (PET).
Medicinal chemistry of new Nature-inspired treatments for Inflammatory Bowel Disease (IBD)
Principal Advisor: Prof Rob Capon (IMB)
Associate Advisor: Dr Jake Begun (Mater Medical Research Institute) and Prof Mark Morrison (UQDI)
Inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis, are debilitating life-long relapsing-remitting diseases of the gastrointestinal tract usually diagnosed in otherwise healthy young adults. Despite multiple approved treatments for IBD, up to 25% of patients will fail current therapies and require surgery to remove diseased parts of their intestine.
Gut bacteria produce bioactive metabolites that are absorbed by the intestine and distributed throughout the body, impacting both local and distant sites. The immune system in the gut is generally tolerant of its associated microbiota. In a healthy gut, bioactives produced by gut microbiota have pro and anti-inflammatory actions, and contribute to maintaining balance. This balance is lost in immune mediated gut disorders such as IBD.
This project seeks to acquire knowledge of and develop anti-inflammatory chemicals produced by the gut bacteria of IBD patients. More specifically, the project will define and optimise novel anti-inflammatory pharmacophores, while identifying molecular targets, binding sites and mechanisms of action.
The successful candidate will join a multidisciplinary, multi-institute research team where, supported by in vitro and in vivo biology, they will be instructed and become proficient in analytical, spectroscopic, synthetic and medicinal organic chemistry.
Applicants should have high level undergraduate training, excellent grades and a passion for organic chemistry.
New chemical space as a source of new drug leads
Principal Advisor: Dr Zeinab Khalil (IMB)
Associate Advisor: Prof Phil Hugenholtz (SCMB), Prof Ian Henderson (IMB) and Prof Rob Capon (IMB)
Microbes have been a new promising source of modern medicines, including antibiotics (e.g. penicillin) and immunosuppressants (e.g. sirolimus) and well as agents to treat cancer (e.g. adriamycin) and cardiovascular (e.g. statins) disease, as well as many more. Recent advances in genomics offer the prospect of exciting new approaches to discovering the next generation of medicines hidden within the Australian microbiome.
To this end in 2020 we launched Soils for Science (S4S) as an Australia wide citizen science initiative, designed to engage the public, to collect 10's of thousands of soil samples from backyards across the nation, from which we will isolate 100's thousands of unique Australian microbes.
This project will annotate the S4S microbe library to prioritize those that are genetically and chemically unique. These will be subjected to cultivation profiling, and fermentation, followed by chemical analysis to isolate, identify and evaluate new classes of chemical diversity.
The successful candidate will join a multi-disciplinary team where, supported by microbiological and genomic sciences, they will gain skills and experience in analytical, spectroscopic and medicinal chemistry – to inform and inspire the discovery of future medicines.
Applicants must have a strong background with outstanding grades in organic chemistry, and with an interest in learning multidisciplinary biosciences.
Strategies Toward Phage-Antibiotic Conjugates
Principal Advisor: Dr Karl Hansford (IMB)
Associate Advisor: Dr Karen Weynberg (SCMB), Prof Ian Henderson (IMB) and Assoc Prof Mark Blaskovich (IMB)
We live in an era where antibiotic resistance is a major threat to global health. In this context there has been a resurgence of interest in using bacteriophages, viruses that infect, lyse and selectively kill bacteria. Antibiotics, by way of their indiscriminate killing action, can cause collateral damage to the microbiome. In contrast, phages are much more specific, targeting a narrow range of bacterial hosts. This perceived benefit is offset by the fact that bacteria readily evolve resistance to phage infection, necessitating the use of phage cocktails to cover different bacterial strains or species. Combining the action of phages and sublethal concentrations of antibiotics can lead to synergistic killing as the bacteria are subjected to different selection pressures. This practice could lead to a reduced reliance on antibiotics, supressing the emergence of resistance and the potential for toxic side effects. To this end, the chemical conjugation of antibiotics to phages represents a novel strategy to precisely deliver antibiotic payloads to sites of infection leading to a dual synergistic killing action by both phage and antibiotic. This project will explore this concept by developing chemical methods to conjugate suitably functionalised antibiotics to phage protein motifs leading to stable constructs designed to release the antibiotic cargo under pre-defined conditions. The resulting phage-antibiotic conjugates will be characterised using in vitro and in vivo methods to determine their effectiveness.
Structural and functional studies of macrocyclic peptides targeting receptors and trafficking molecules essential for SARS-CoV-2 infection
Principal Advisor: Prof. Brett Collins (IMB)
Associate Advisor: Mehdi Mobil (CAI, UQ) and Larisa Labzin (IMB)
This project focuses on the development and characterisation of small stable ‘macrocyclic’ peptides that target key receptors and intracellular complexes important for normal cellular physiology and targets in disease including SARS-CoV-2 infection and cancer. Using the “RaPID” screening approach we are identifying high affinity macrocyclic peptides with activity against proteins that regulate membrane trafficking and cellular uptake. For an example of how this is done see our recent article [1]. There are a number of potential targets that could be studied in this project for which preliminary screens have been performed. These include the neuropilin receptor (NRP1) recently identified as important for cellular infection of SARS-CoV-2 [2], and also a drug target in certain cancers because of its role in creating blood vessels in the tumour environment (angiogenesis). It is also bound by the scorpion toxin ClTx which is being developed as a marker for brain tumours, and new macrocyclic peptides may provide high affinity molecules for improved glioma diagnosis and therapy [3]. Another possible target is the ‘Commander’ complex which regulates the recycling of transmembrane proteins from intracellular organelles to the cell surface. Commander has also been identified as important for SARS-CoV-2 infection, and additionally is mutated in human X-linked intellectual disability.
The project will involve a wide array of techniques from peptide synthesis, biophysical studies of protein-protein interactions, structural biology including NMR, crystallography and cryoEM. Successful discovery of inhibitory peptides might also allow testing in cellular models of infection by SARS-CoV-2. The candidate will benefit from some background in biochemistry, structural biology and/or cell biology. Collectively, this project will deliver new insights, tools, and molecules that underpin key areas of unmet clinical need. The project will be supervised by experts in structural biology, peptide characterisation and membrane interactions, and virology and will includes opportunities for internships with industry partners where appropriate.
Targeting sodium channel accessory proteins for treatment of chronic pain
Principal Advisor: Prof Irina Vetter (IMB)
Associate Advisor: Assoc Prof Mehdi Mobli (CAI)
Chronic pain remains an area of significant unmet medical need. Voltage-gated sodium channels expressed preferentially in primary sensory afferents are recognised as important analgesic targets. Naturally occurring toxins and venom-derived peptides have evolved to target sodium channels channels with high specificity and potency, and thus provide unique opportunities to probe the structure and function of this important class of transmembrane proteins and as potential therapeutics. However, most studies have focused on the pore-forming α subunit of the channel, although it is well known that functional channels occur as multi-protein assemblies.
In this project, students will implement multidisciplinary and innovative approaches using toxins as tool molecules to investigate the role of a recently discovered toxin-binding accessory protein that regulates channel function.
Students will gain experience with peptide synthesis, patch-clamp electrophysiology, sensory neuron culture, nuclear magnetic resonance and in vivo behavioural assays to tackle the global problem of unrelieved chronic pain with innovative molecules targeting peripheral sensory neuron function.
Targeting the Biogenesis of Resistance Enzymes to Combat Antimicrobial Resistance
Principal Advisor: Dr Anthony Verderosa (IMB)
Associate Advisor: Assoc Prof Mark Blaskovich (IMB) and Prof Vito Ferro (SCMB, UQ)
Bacterial enzymes represent a major resistance mechanism driving the emergence of antimicrobial resistance. Inhibitors that directly bind to resistance enzymes and impede their function are an obvious strategy to overcome enzyme-mediated resistance; however, only the highly successful β-lactamase inhibitors have reached clinical use. Drawbacks of this strategy include the specificity of these inhibitors to only one type of resistance enzyme, and the potential for subsequent mutations to quickly restore the enzymatic activity, as the enzyme is still produced. This project explores an innovative new approach for simultaneously deactivating multiple resistance enzymes to restore the efficacy of multiple classes of antibiotics. Instead of directly targeting the resistance enzyme, this project aims to disable the machinery required for resistance enzyme biogenesis, ultimately preventing the active enzyme from being produced. We are looking for a proficient and enthusiastic synthetic chemist interested in medicinal chemistry and microbiology to work on one of the major aspects of this project.
The project will entail the design, synthesis, and microbiological evaluation of dual-acting antibiotic-biogenesis inhibitor hybrids, where antibiotic activity is supplemented with other mechanisms. Antibiotics will be coupled with inhibitors previously shown to inhibit resistance enzyme biogenesis. These hybrids should simultaneously deactivate resistance mechanisms and eradicate subsequently susceptible bacteria.
Using genomics to inform discovery of new peptide drug for common gastrointestinal disorders
Principal Advisor: Prof. David Craik (IMB)
Associate Advisor: Prof Naomi Wray
There are many advantages of peptide-based drugs including exquisite specificity to in vivo targets, resulting in exceptionally high potencies of action and relatively few off-target side effects (Craik et al, 2013). Limitations of peptide drugs are low systemic stability, poor membrane permeability, low bioavailability and high production costs.
However, these limitations may be overcome for drugs where the target tissue is the gastro-intestinal tract.
The Craik lab (Chemistry and Structural Biology Division) at IMB discovers and re-engineers novel peptides for applications in drug design and agriculture (Wang et al, 2018). Their work has the potential to lead to new drugs for the treatment of a wide range of diseases, including cancer, cardiovascular disease, metabolic disease, infectious disease and pain.
Researchers within the Wray lab (Genetics and Genomics division) at IMB have recently conducted in depth genome-wide association studies for disorders of the gut, specifically peptic ulcer disease and gastro-oesphogeal reflux disease (Wu et al, 2021), diverticulosis (in preparation), integrating with published results for the inflammatory bowel diseases (IBDs) of Crohn’s Disease and Ulcerative Colitis.
In this project the student would use results from genetic studies of gut disease to inform discovery of peptide drugs that specifically target gut tissue and would be jointly affiliated with the Craik and Wray labs.
The ideal candidate will have Honours in chemistry, with an interest in genomics and computational approaches. In the first 6 months the candidate will learn methods to interpret results of genetic association studies and integrate them with the ever-increasing resources of omics data (e.g., Nasser et al, 2021). Armed with this omics toolkit the candidate will undertake a drug design project to develop peptide-based lead molecules to modulate gut targets of interest.
Venom-derived peptides as novel analgesic leads
Principal Advisor: Prof. Irina Vetter (IMB)
Associate Advisor: Dr Richard Clark (SBMS)
Voltage-gated sodium channels are well-validated analgesic targets, with loss-of-function mutations leading to an inability to sense pain, but otherwise normal physiology and sensations. However, efforts to mirror these genetic phenotypes with small molecule inhibitors have highlighted that both selectivity over ion channel subtypes and mechanism of action are key considerations for the development of safe and effective analgesics.
This project will leverage the exquisite potency and selectivity of peptide sodium channel modulators from venoms for the rational development of novel, safe and effective molecules with analgesic activity.
Students will gain experience with peptide synthesis, patch-clamp electrophysiology, sensory neuron culture, microscopy and in vivo behavioural assays to tackle the global problem of unrelieved chronic pain with innovative molecules targeting peripheral sensory neuron function.
The discovery and development of highly stable venom-derived peptide drug leads
Primary advisor: A/Prof. Markus Muttenthaler
Associate advisor: A/Prof. Johan Rosengren
Venoms comprise a highly complex cocktail of bioactive peptides evolved to paralyse prey and defend against predators. The homology of prey and predator receptors to human receptors renders many of these venom peptides also active on human receptors. Venoms have therefore become a rich source for new neurological tools and therapeutic leads with many translational opportunities.
This project covers the discovery, chemical synthesis, and structure-activity relationship studies of venom peptides, with a specific focus on gastrointestinal stability and drug targets in the gut. Venom peptides are known for their disulfide-rich frameworks supporting secondary structural motifs not only important for high potency and selectivity but also for improved metabolic stability. While primarily studied for their therapeutic potential as injectables, this project will break new ground by investigating evolutionarily optimised sequences and structures that can even withstand gastrointestinal digestions, thereby providing new insights for the development of oral peptide therapeutics targeting receptors within the gut. These therapeutic leads will have enormous potential for the prevention or treatment of gastrointestinal disorders or chronic abdominal pain.
The candidate should have a degree in synthetic chemistry, biochemistry or pharmacology, good hands-on laboratory skills, and strong ambition and work ethics. The candidate will be involved in solid phase peptide synthesis, medicinal chemistry, mass spectrometry, NMR structure determination, CD studies, structure-activity relationship studies, gut stability assays, and receptor pharmacology.
Venom-derived sodium channel inhibitors as drug leads for motor neuron disease
Principal Advisor: Dr Fernanda C Cardoso
Associate Advisor: A/Prof Mark Bellingham (SMBS) and Professor Glenn King
Motor neuron disease (MND) is a neurodegenerative condition caused by progressive loss of motor neurons leading to paralysis and death. Investigation of ion channels in motor neurons unravelled a cluster of voltage-gated sodium (NaV) channel subtypes playing key role in the pre-symptomatic stages of this disease. Spider-venoms are an exceptional source of peptides modulating NaV channel with higher potency and selectivity than small molecules such as the drug riluzole used in the treatment of MND.
This project involves systematically interrogating spider venoms via high throughput cellular screens and assay-guided fractionation to discover spider-venom peptides that selectively target central ion channels in motor neurons and therefore have the potential to reverse MND.
This project involves multidisciplinary approaches in discovery, characterization, and structure-function studies of bio-active compounds in spider venoms and other natural repertoires. PhD scholars will develop skills in manual and automated whole-cell patch clamp electrophysiology, ex vivo electrophysiology in motor neurons, high performance liquid chromatography, mass spectrometry, recombinant expression, peptide synthesis, amongst other state-of-the-art methods and techniques. Students will author papers and be involved in writing and figures preparation for research publications from their work.
Structural and cellular analysis of Rab GTPases for drug discovery in cancer.
Principal Advisors: Prof Jennifer Stow (IMB)
Associate Advisor: Dr Quan Nguyen (IMB) and Prof Brett Collins (IMB)
Small GTPases of the Rab protein family control membrane trafficking and signalling inall eukaryotic cells. Rabs function with the help of accessory proteins that switch them on and off, and then act to recruit and activate effector protein complexes in many different cellular pathways. Recently, several Rabs have emerged as oncogenes in cancer. Rab13 for instance is overexpressed in cancers, including aggressive forms of breast cancer, where it drives metastasis and tumour growth. Rab14 has been implicated in various cancers including lung cancer, and its effector Nischarin is noted tumour suppressor in breast cancer.
Combined with experimental approaches, new machine learning computational methods are revolutionising structural biology and our understanding of how proteins interact with each other. In this project you will undertake in silico interrogation of Rabprotein-protein interactions with known or potential effectors and accessory proteins. These interactions will then be verified through imaging for colocalization and functional assays in cancer cell lines and spheroids. Spatial transcriptomics and spatial proteomics on sections of tumour samples will provide direct evidence for protein interactions in cancer.
Together these approaches will allow the identification, characterization and optimization of protein binding sites as new targets for drug development, preclinical analysis and potential therapeutic intervention.
This project will involve a close collaboration between three groups across two divisions at IMB, offering students the opportunity for cross-disciplinary training in cancer research using in silico structural modelling, cell and cancer biology and tumouranalysis.
Noninvasive peptide tracers for improving immunotherapy outcomes
Principal Advisor: Dr Conan Wang (IMB)
Associate Advisors: Prof David Craik (IMB) and Prof Kristofer Thurecht’s (AIBN)
Non–small cell lung cancer (NSCLC) is the leading cause of cancer mortality, with nearly 1.6 million cancer-related deaths each year worldwide. In Australia, NSCLC is the most prevalent form of lung cancer (64% male and 61% female). At diagnosis, one in three NSCLC patients are inoperable.
Immune checkpoint inhibitors are cancer drugs that help the immune system fight cancer and have revolutionised treatment of NSCLC, but predicting patient benefit using approved core needle biopsies are erroneous and painful. Core needle biopsies are hampered by intra- and inter-tumoral heterogeneities. They are impractical for metastatic and risky for advanced cases.
This project aims to develop next-generation molecular imaging agents for patient-friendly, safe and accurate whole-body visualisation of tumours, allowing clinicians same-day feedback to select the proper treatment and monitor progress. The molecules will be suitable for noninvasive imaging by positron emission tomography (PET), which provides quantitative, real-time assessment for patient stratification. Methods to be explored in this project span across chemistry, biology, and physics.