Global Challenges PhD Projects

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Please peruse the projects below, across the tabs.

Project title

Principal advisor

Project description

Primary Research Areas

Antibiotic Conjugates: Joining Together to Fight Antimicrobial Resistance A/Prof Mark Blaskovich With a near-empty antibiotic pipeline and growing antimicrobial resistance, there is a global search for novel approaches to treat infections. This project will investigate three innovative new approaches to address this urgent unmet need, all based on a core concept where existing antibiotics are functionalised so they have a chemical handle that can be used to attach other moieties. It builds on an advanced platform of bespoke derivatised antibiotics that we have developed over the past five years. We are looking for a proficient and enthusiastic synthetic chemist interested in medicinal chemistry to work on one or more aspects of the overall project:
1)  Antibiotic-adjuvant hybrids: Supplement antibiotic activity with other mechanisms. Antibiotics will be coupled with moieties that increase or supplement the parent antibiotic efficacy, creating antibiotic-conjugated adjuvants. Siderophores can increase antibiotic cellular penetration. Biofilm disrupting agents can improve the efficacy of antibiotics that struggle to penetrate and kill biofilms associated with resistance. Antivirulence factors target pathogen excretions that promote adhesion, invasion and colonisation.
2) Immune activation: Leverage the immune system to help fight infections. This aim will explore how we can activate the immune system to more effectively eliminate infections, by using antibiotics as markers that label bacteria for destruction by triggering an antibody-based immune response. Based on the Antibody Recruiting Molecule approach that has been developed for other diseases, we will functionalise surface-binding antibiotics by linking them to small molecules capable of eliciting an antibody response and bacterial killing by human phagocytes.
Promising candidates through a validated progression of assays that assess both antimicrobial activity and drug-like properties, culminating in testing for in vivo efficacy, toxicity and pharmacokinetics.
Synthetic and Medicinal chemistry
Circadian regulation of antibiotic efficacy and toxicity A/Prof Frederic Gachon The circadian clock is an endogenous timing system that orchestrates most aspects of physiology and behavior. This includes the regulation of the immune system and drug detoxification. Consequently, the circadian clock likely plays a role in the regulation of the capacity of antibiotic to fight bacterial infection. The aim of this project is to define the impact of circadian rhythm on antibiotic efficacy, but also to use this regulation to improve their efficacy while also reducing their side effects. Infection

Circadian rhythms

Pharmacology

Pharmacokinetics
Combating bacterial infections through reprogramming of innate immunity. Prof Matt Sweet The sophisticated cellular and molecular networks of our immune system defend against a wide range of microorganisms that would otherwise cause infectious disease. Innate immune cells such as macrophages use a plethora of direct antimicrobial responses to destroy bacterial pathogens. Conversely, many bacterial pathogens subvert macrophage antimicrobial pathways to colonise the host and cause disease. The interplay between macrophages and bacterial pathogens is thus a key determinant of infectious disease outcomes. This PhD project aims to precisely understand, and pharmacologically amplify, specific macrophage antimicrobial responses as a ‘host-directed’ strategy to combat antibiotic-resistant bacterial infections. Immunology & Cell Biology

Chemistry & Pharmacology
Developing predictive models for discovering novel classes of Gram-negative antibiotics using deep learning Dr Johannes Zuegg There is an urgent need for new antibiotics to treat infections caused by multidrug-resistant (MDR) and extensively drug-resistant (XDR) pathogens particularly, Gram-negative (G-ve) Pathogens. Novel antibiotics that will be effective against G-ve pathogens are particularly hard to find, owing to the extracellular membrane. This membrane makes it difficult for the entry of antibiotic compounds. This work aims to develop predictive models for G-ve membrane penetration and antibacterial activity. The project will be focused on organometallic complexes, which we have recently identified as a promising novel class of antibiotics, and which have been excluded from machine learning approaches to date due to their structural complexity.
Candidates selected for this project would have a background in at least one of the following disciplines and an interest in an interdisciplinary project spanning all three areas: organic chemistry, chemoinformatics, machine learning.
Organic and medicinal chemistry

Chemoinformatics

Machine learning. 
Developing vaccines for Gram-negative pathogens Prof Ian Henderson Antibodies to the Gram-negative bacterial surface, induced after natural infection or vaccination, save millions of lives each year. Achieving wide-ranging immunity to multiple, related pathogens is clearly desirable but is not always straightforward. The only licensed single-antigen vaccines against diseases caused by bacteria are based on capsular polysaccharides or exotoxins. When these are not utilized then vaccines become increasingly antigenically complex yet with little empirical rationalization as to which antigens are protective. Using genetic techniques, combined with models of infection and vaccination, this project will probe which antigens can be combined to elicit protection against the model organism Salmonella enterica, in hopes of designing more efficacious vaccines to combat antibiotic-resistant bacteria. Microbology

Immunology
Gram-negative bacterial pathogens induce inflammatory responses through cross-talk between PI3K and inflammasome pathways Prof Kate Schroder Gram-negative bacteria can invade and colonise our immune cells. This activates multiple pathogen-detection systems in the cells, including inflammasomes which are multi-subunit spiralled hubs that trigger pore-forming complexes, the release of inflammatory cytokines and the death of infected cells, as dramatic responses to limit infection. Other pathogen-detecting receptors deploy PI3K – a druggable family of lipid kinases, acting at cell ruffles and projections and on endocytic membranes to recruit signalling kinases Akt and mTOR which control pathways for cell survival and inflammation. This project will examine points of intersection between bacterially-activated inflammasome and PI3K by investigating cell signalling pathways, membrane domains and cell and bacterial fates. The project aims to devise multi-drug strategies for targeting host cells for the control of infection and inflammation Immunology

Molecular biology

Cell biology
Harnessing the Bacterial Proteolytic Machinery for Next Generation Antimicrobials Dr Karl Hansford  Despite the critical role of antibiotics in modern day medicine, the discovery of new antimicrobial agents over the last 50 years has not kept pace with the emergence of bacterial resistance. This is further hampered by our limited understanding of how to breach the bacterial envelope with new chemical matter. This constant threat to our antibiotic armamentarium contrasts sharply with the many technological advancements made in drug discovery across other therapeutic areas.
One such discovery is the concept of induced elimination of target proteins, exemplified by the Proteolysis Targeting Chimeras (PROTACs): bi-functional small molecules that tag proteins for degradation by the eukaryotic proteasome. This enabling technology has paved the way for pursuing targets once considered “undrugabble”.
There is considerable interest to apply targeted degradation principles to bacteria. To date this has not been done. Bacteria utilise many housekeeping proteases to tightly regulate cellular protein levels. The highly conserved caseinolytic protease P (ClpP) is an illustrative example found in multiple bacterial species; its overactivation by small molecules leads to aberrant degradation of bacterial proteins, resulting in cell death. This project will explore novel approaches to engage bacterial proteases such as Clp to enable the inducible, selective and efficient degradation of target proteins in bacteria. Candidates should have a strong interest in medicinal chemistry and chemical biology.
    
Organic and medicinal chemistry

Chemical biology

Immunology
How does cannabidiol kill bacteria? Dr Alysha Elliott Cannabidiol (CBD), the main non-psychoactive component of cannabis, is the prototypical member of a promising new class of antibiotics with excellent activity against most Gram-positive, and some key Gram-negative,pathogens.  Initial studies show it acts by causing membrane damage, but the exact mechanism by which this occurs is not clear .This project will apply a range of genetic and molecular methodologies to investigate exactly how CBD works, why resistance is very slow to develop, and why only certain types of Gram-negative bacteria are susceptible. Microbiology

Molecular biology

Pharmacology
How do intracellular pathogens control the inflammatory response Prof Ian Henderson Inflammasomes are signalling hubs that assemble when specific innate immune receptors sense microbial infection. Recently, we discovered that Salmonella enterica is capable of supressing the host inflammatory defence pathwyas to enable cytosolic survival. This pathway harnesses cellular metabolism and offers potential for eradicating intracellular pathogens. The project will use a combination of molecular and cell biology, coupled with in vivo models, to elucidate mechanisms of inflammasome-mediated microbial killing so that we can harness these strategies to combat antibiotic-resistant bacteria. Microbology

Immunology
Identification of new targets for antimicrobial development Prof Ian Henderson The development of next-generation antibiotics requires the identification of new bacterial targets beyond those inhibited by the current repertiore of antimicrobial agents. This project will focus on seeking components of bacterial biological pathways that are critical for bacterial survival and virulence, then applying medicinal chemistry to screen for potential inhibitors and optimise their antibacterial effectiveness. Microbiology

Microbial genetics

Chemical biology

Molecular biology
Imaging bacteria: Deciphering antimicrobial resistance with chemical probes A/Prof Mark Blaskovich Bacteria are becoming resistant to every known antibiotic, largely due to inappropriate agricultural and human use, leading to multi-drug resistant ‘superbugs’ that threaten a global pandemic with devastating implications. New antibiotics are urgently needed, particularly for Gram-negative bacteria, along with new diagnostics capable of quickly identifying resistant bacteria. For this to occur we need to improve our fundamental understanding of how antibiotics work and interact with bacteria. This project will utilise a suite of mechanistic antibiotic-derived probes to investigate the interactions of bacteria, antibiotics and the immune system, both in vitro at the cellular level, and in vivo, in mouse models of infection. Microbiology

Chemical biology

Molecular biology

Pharmacology
Inflammasomes defend cells from invasion by Gram-negative bacteria Prof Kate Schroder Inflammasomes are signalling hubs that assemble when specific innate immune receptors sense microbial infection. One newly-described inflammasome is critical for host defence against cytosolic Gram-negative bacteria. This pathway employs an extraordinary signalling mechanism, in which inflammatory caspases directly interact with bacterial lipopolysaccharide (LPS) to induce caspase protease function. Caspase activation by LPS induces a rapid and spectacular form of cell death (‘pyroptosis’) that activates antimicrobial defence programs, and microbial killing. This project will use a combination of molecular and cell biology, coupled with in vivo models, to elucidate mechanisms of inflammasome-mediated microbial killing so that we can harness these strategies to combat antibiotic-resistant bacteria Molecular biology

Cell biology

Microbiology

In vivo models
New antibiotics from Australian soil microbes Prof Rob Capon  This HDR project will explore a library of microbes isolated from Australian soil samples collected under the Soils for Science citizen science initiative. Solvent extracts of analytical scale microbial cultures will be subjected to antibiotic profiling against a panel of drug resistant clinical pathogens, and chemical profiling using a mass spectrometric molecular networking strategy. Prioritised extracts containing promising new classes of antibiotic will be further assessed using a miniaturised media MATRIX cultivation profiling approach, to arrive at optimal conditions for scaled up cultivation. Prospective new antibiotics will be produced, isolated and characterised, with molecular structures elucidated by detailed spectroscopic and chemical analysis. Medicinal chemistry guided structure activity relationship studies will optimise and define new antibiotic pharmacophores, which will be assessed for potency, selectivity and mechanism of action.  Organic natural products

Medicinal chemistry

Microbiology
Targeting bacterial biofilms in patients with gastrointestinal disorders A/Prof Markus Muttenthaler Gastrointestinal disorders affect 10–15% of the Western population, reduce the quality of life and result in substantial socioeconomic costs. Recently, we have observed bacterial biofilms in the gastrointestinal tract of IBD and IBS patients, but their disease relevance, function and composition remain unknown. This project aims to (i) use various analytical techniques to profile these gut biofilms and (ii) to develop biofilm-specific modulators to explore novel therapeutic strategies. Techniques likely to be acquired: solid phase peptide synthesis, organic chemistry, medicinal chemistry, high-performance liquid chromatography, mass spectrometry, proteomics, nuclear magnetic resonance spectroscopy, cell culture and pharmacological assays, gastrointestinal stability assays, antimicrobial and biofilm assays.

Organic, medicinal and analytical chemistry

Proteomics

The role of lipid droplets in combatting bacterial infection Prof Rob Parton Successful defense against pathogens is critical for survival. Lipid droplets are dynamic and complex organelles that provide eukaryotic cells with substrates for energy metabolism, membrane synthesis, and production of lipid-derived molecules. Lipid droplets have been hijacked by pathogens to provide lipids during infection. We have recently demonstrated that the pathogen-lipid droplet interaction is harnessed by the host to organise an intracellular first line of defence. Mammalian lipid droplets have a complex and regulated protein-mediated antibiotic activity. In this project we will investigate whether targeting of newly-developed antibiotics to lipid droplets can enhance their anti-bacterial activity against a range of pathogens. Chemical biology

Microbiology

Molecular biology

Immunology
Theta-defensins as novel antimicrobials and immunomodulators Prof David Craik θ-Defensins are macrocyclic host defense peptides  found  exclusively in non-human primates and have potent antimicrobial activities by directly affecting host–pathogen interactions (e.g. viral entry) or as immune modulators (e.g. attraction of macrophages). The broad aim of this project is to explore the biochemistry and applications of θ-defensins and thus develop a foundation for medically harnessing their exciting pharmaceutical properties for the treatment of infectious and inflammatory disease. Specifically, we aim to i) delineate the mode-of-action and the spectrum of activities of θ-defensins, ii) engineer them with new designer bioactivities and iii) identify and characterise the enzyme machinery responsible for θ-defensin biosynthesis.
This multidisciplinary project would be suitable for candidates with interests in biochemistry, structural biology, molecular biology, analytical biochemistry and/or organic chemistry.
Biochemistry

Structural biology

Molecular biology

Analytical biochemistry 

and/or Organic chemistry
Understanding the impact of temporal variability in antibiotics and resources on the evolution of antibiotic resistance in microbial communities Dr Andrew Letten In both agricultural and medical scenarios, antibiotics are typically delivered in intermittent pulses. Despite a substantial body of literature focusing on the optimisation of dosing regimes (i.e., dose timing and frequency) in the context of pharmacodynamics, the implications of different temporal patterns of antibiotic delivery on the evolution of antibiotic resistance in microbial communities has thus far gone largely ignored. Drawing on classical mathematical models of resource competition and emerging ecological theory, we have recently shown how different temporal patterns of resource and antibiotic supply can have diametrically opposing consequences for competitive outcomes and coexistence between antibiotic resistant and sensitive bacteria (Letten et al. 2021 Nat. Eco Evo). The goal of this project is to go beyond the theory and test how well we can predict coexistence between resistant and sensitive bacteria under the highly variable environmental conditions typical of most microbial systems.

Microbiology
 

Ecology and Evolution


Applied mathematics

Contact

Dr Madhavi Maddugoda
Strategic Advisor, Research Training

  m.maddugoda@uq.edu.au


Get notified when the next scholarship round opens

Project title

Principal advisor

Project description

Primary Research Areas

A global quantitative genetic network for Escherichia coli Prof Ian Henderson Genetic interactions occur when mutations in two or more genes combine to generate an unexpected phenotype. A synthetic lethal genetic interaction occurs when two mutations, neither lethal individually, combine to cause cell death. Synthetic lethal interactions are of particular interest because they can be harnessed to identify new antibiotic targets. For example, if gene X and gene Y are nonessential but together they are synthetically lethal, then a lethal effect can be achieved by combining a small molecule that inhibits the product of X with a small molecule that inhibits the product of Y. Using our exceptionally high resolution mutagenesis technique we will study the genetic interaction of every gene across the whole chromsome at the resolution of the codon. The anticpated 4 billion interactions generated by this process will provide a tool to discover leads for gene function and drug action including genes involved in multiple antibiotic resistance and the synergy between antibiotics. Microbial genetics

Bioinformatics

Genome sequencing
Adaptation to Discover Novel Heart Disease Therapeutics Dr Nathan Palpant This project will determine how the heart adapts to high-altitude, low-oxygen environments to protect cardiac viability and function under extreme stress. Human populations living in high-altitude hypoxic environments have shown generational gene adaptations compared to lowland cohorts. These extreme environmental stresses result in adaptive responses to maintain cell and organ viability and function. We hypothesise that genes adapted to high altitude provide a unique approach to discover novel genes or pathways for protecting organs from acute ischemic stresses. This project will use genetic data and cells derived from individuals from lowland versus highland populations in China and Central America to identify genes selected for high-altitude survival. These genes can be used to identify novel molecules that block these pathways as a path toward discovering novel drugs to treat patients who suffer from acute injuries like heart attacks. Collectively, this project aims to identify genes associated with adaptation to conditions of low oxygen to develop drugs against these targets as next-generation therapeutics for acute cardiac ischemic injuries. Cell biology

Human statistical genetics

Protein biochemistry
A spatial multiomic platform to delineate drivers of splenic aging   Dr Christian Nefzger Ageing is broadly defined as the time-dependent functional decline that affects most living organisms. On a cellular level, this functional decline appears to have a largely non-genetic basis, as it can be manipulated and even reversed by pluripotency induction. However, a proper mechanistic understanding of how age-related changes (both extrinsic and intrinsic) potentiate cellular dysfunction is largely missing. Aged CD8 T-cells, have a reduced functional capacity to responded to pathogens and malignant cells, reflected by a compromised capacity to expand. The environmental component of this ageing phenotype is evidenced by the fact that young T-cells acquire the proliferation effect when transplanted into the aged splenic milieu. Conversely transplantation of age T-cells into young hosts does not resolve it, demonstrating the cell intrinsic component. Using this model system, the project will establish a platform to molecularly study splenic ageing at the organ and individual cell level to unravel the cell extrinsic and intrinsic drivers (and their interplay) of the ageing phenotype. This will involve the use of spatial transcriptomic analyses (including the study of age-altered cell-cell communications) employing a data set already present in the host laboratory. In addition, matched single cell multiome data (paired RNAseq/ATACseq data set) will be mapped against spatial transcriptomic data to enable spatial epigenetic analyses. To properly disentangle cell intrinsic and extrinsic potentiators of T-cell ageing, heterochronic transplantation experiments followed by molecular profiling will also be performed. The outcomes of this project will provide a comprehensive picture of splenic ageing by generating a molecular and spatial ageing road map for this organ and its resident T-cells. This will set the basis for future strategies to improve the function of aged cells. 

Computational biology

Dry lab project

Deciphering the DNA-protein interactions that reset the ageing clock during reprogramming Dr Christian Nefzger Ageing is broadly defined as the time-dependent functional decline that affects most living organisms.  Findings from the field of transcription factor (TF)-mediated reprogramming point towards epigenetic changes as fundamental drivers of the ageing process. The fact that mature cell types can be reprogrammed back towards a pluripotent state (so called iPS cells) by the forced expression of four transcription factors (Oct4, Klf4, Sox2, c-Myc [OKSM]), a process that resets the epigenome, demonstrates that development is not unidirectional. Furthermore, iPS cell generation has recently been expanded to functionally compromised aged blood stem cells. Considering that the resulting iPS cells were able to generate young healthy animals with a normal hematopoietic system and life spans, the ageing process per se, at least on a cellular level, appears to be an epigenetic phenomenon that can be manipulated. The project’s aim is to identify the DNA-protein interactions responsible for the gradual resetting of the epigenetic ageing clock of somatic cells during iPS cell generation. This will help set a basis for future strategies to directly improve the function of aged cells without a need for forced OKSM expression/pluripotency induction. 

Molecular biology 

Cell biology

Biochemistry

Engineering Cells by Design Dr Nathan Palpant This program of research aims to design and control the decisions and functions of human cells. We are using the innate capabilities of pluripotent stem cells to make human cell types with programmable functions. While cells provide extraordinary capabilities enabling complex organisms to function, evolutionary processes have constructed complex safeguards to ensure cell decisions and functions are protected. This project aims to deconstruct genetic mechanisms controlling cells, disrupt safety systems encoded in the genome, perturb cell inputs and link them to cell responses, and build prototype programmable human cells.  The long-term vision is to design custom cells with desirable properties to address important medical and biotechnological needs. There is significant discovery required to realise these outcomes. We need to understand how the genome controls cell decisions. Which factors are the important cell differentiation decision makers? What barriers are put in place to keep their activity at bay until needed? What signals lift those barriers to enable cell decisions to proceed? We need methods integrating this knowledge to generate cells designed with specific properties and functions. Computational bioinformatics

Cell biology

Genomics.
From decoy receptors to drug candidates: A genetic study Dr Joana Revez Cytokines are signalling proteins that play a central role in cell-to-cell communication in immune responses. These signalling molecules bind to their target cells through cognate receptors and trigger intracellular pathways that modulate the activity of the cell, leading to cell activation, differentiation and/or proliferation. Some cytokines can also bind to decoy receptors (DRs). DRs bind to ligands with high affinity and specificity, but they are not structurally able to transmit signal to target cells. Consequently, DRs modulate cytokine bioavailability. When dysregulated, DRs can lead to disease by interfering with immune cell-to-cell communication. Importantly, DRs represent easy targets for therapeutic intervention (e.g., with antibodies). This project will leverage state-of-the-art genetic datasets and advanced computational methods to assess the consequences of genetic variation in genes that code to decoy receptors and to evaluate their suitability as new drug targets in a range of disease traits. Computational biology

Genetics

Immunology

Molecular biology
Genetic factors influencing response to endocrine and circadian perturbations in human disease Dr Frederic Gachon Our recent results suggest that the mutual mis-regulation of the circadian rhythms and the Hypothalamus-Pituitary-Gonadal (HPG) axis is a common feature of numerous pathologic conditions. However, a direct link between mis-regulation of the HPG axis and chronodisruption has not yet been demonstrated. The goal of the project is to define how chronodisruption-associated endocrine perturbations influence the pathophysiology of human diseases, and to decipher the genetic and epigenetic factors influencing these perturbations. Genomics

Genetics

Epigenetica

Circadian rhythms

Human diseases
Genetics of left handedness Prof David Evans  Handedness refers to the preferential use of one hand over the other. Conversely, ambidexterity refers to the ability to perform the same action equally well with both hands. Hand preference is first observed during gestation as embryos begin to exhibit single arm movements. Across the life span, the consistent use of one hand leads to alterations in the macromorphology and micromorphology of bone, which results in enduring asymmetries in bone form and density. At the neurological level, handedness is associated with the lateralization of language (the side of the brain involved in language) and other cognitive effects. The prevalence of left-handedness in modern western cultures is approximately 9% and is greater in males than females. While handedness is conceptually simple, its aetiology and whether it is related to brain and visceral (internal organ) asymmetry is unclear. Using data from the UK Biobank, 23andMe and the International Handedness Consortium, we recently conducted the world’s largest genetic study of handedness in over 1.7 million individuals (Cuellar-Partida et al 2020). We found 41 genetic loci associated with left-handedness and 7 associated with ambidexterity (P < 5 × 10−8). We would now like to take this work forward and use this resource to investigate the relationship between handedness and a variety of life outcomes including mortality and common complex diseases. The successful candidate will gain experience across a wide range of advanced statistical genetics methodologies including Mendelian randomization (a way of using genetic variants to investigate putatively causal relationships), genome-wide association analysis (GWAS), genetic restricted maximum likelihood (G-REML) analysis of genome-wide data which can be used to partition variation in phenotypes into genetic and environmental sources of variation, and instrumental variables analysis (using natural “experiments” to obtain information on causality from observational data). Statistical Genetics

Epidemiology

Psychology
Genomics of Caveolae-associated Disease

Prof Rob Parton

&

Dr Allan McRae
(co-advisors)

The surface of human cells is covered in tiny pits called caveolae. Caveolae have been implicated in regulation of cell growth and in maintaining the balance of lipids in the cell. Defective caveolae in human patients are associated with a number of different human disease conditions including various forms of cancer, lipodystrophies (lack of fat tissue), muscular dystrophies, and cardiac disease. With the discovery of the major proteins of caveolae, including the caveolins and cavins, and the availability of a wealth of human genome information we are now able to start to systematically explore the contribution of caveolae-associated proteins to a large range of disease conditions. This project will involve mining genomic information for diseases linked to caveolar dysfunction and the development of cellular and animal models to dissect the contribution of caveolae to human disease conditions. Computation

Cell biology

Cellular models of disease
 
How do patient-derived mutations affect nervous system development? Dr Melanie White The brain and the spinal cord control most of the functions of the body and the mind, yet the dynamics of how they first form is poorly understood. Both structures arise from a common precursor, the neural tube, which forms during the first month of human embryonic development. Failure of the neural tube to form correctly causes severe congenital abnormalities called neural tube defects (NTDs). Mutations have been identified in many patients with NTDs but how they disrupt nervous system development is poorly understood due to the inaccessibility of the embryo. This project aims to use induced pluripotent stem cells to establish an in vitro organoid model of human neural tube development. Patient-derived mutations will be introduced using CRISPR and the consequences for neural development will be examined using a range of techniques. These may include live confocal microscopy, transcriptomics analysis, mechanobiology approaches and avian xenotransplantation models. By revealing how gene mutations affect the cellular mechanisms driving neural tube formation, this project will address a major gap in our understanding of the aetiology of common human birth defects and may provide potential avenues for diagnosis and treatment of NTDs. Cell biology

Stem cells

Developmental biology

Neuroscience
How drug treatment affects tumours and their host ecosystem? Dr Quan Nguyen 

Drugs used in chemotherapies and targeted immune therapies often affect multiple cell types and cells in different parts of the body. Systematic understandings of cancer drug effects on different cells across body is lacking. These cells respond differently to treatment, which often leads to lack of response, resistance, side effects, and/or recurrence. Thus, we propose a novel concept to assess cancer drug effect at an ecosystem level. Cancer ecosystem consists of three scales, including: individual cells, microenvironments, and the whole organism (macroenvironment).

While a great amount of research is being focused on cancer microenvironment, very limited work has systematically looked at effects across all the three scales. This project will address this unmet clinical demand.

Recent databases like the Human Cell Atlas contain information of over 2500 cell types across the whole body. We will use such information to predict cells that are potentially affected by a drug, for example those expressing targeted receptors. We will use spatial transcriptomics to measure all cell types within undissociated tissue in treated vs untreated samples and compare differences in tissue microenvironments. Advanced imaging approaches will be used to capture molecular effects by monitoring selected biomarkers at single cell resolution. Together, we will enhance understanding on the variation in individual cells, among neighbouring cells in microenvironments and among distant cell types. Such understandings are needed for effective and safe treatment of cancer patients.

Bioinformatics

fenomics technologies

Cancer biology, cell biology

Imaging

 

Identifying genetic "dark matter" Prof Ian Henderson Essential genes are targets for drug development, thus it is crucial to have a full
understanding of which genes are essential. The exceptionally high resolution of our mutagenesis technique allows us to identify regions across genomes that are essential but missed using targeted gene disruption methods that focus only on annotated coding sequences.  In this project, we will harness genetic tools to identify and validate small open reading frames that are essential, or conditionally essential under various environmental selections, and have traditionally been ignored as protein coding elements.
Microbial genetics

Biochemistry

Genome sequencing

Bioinformatics
Identifying vascular cell types and genes involved in human skeletal disease

Dr John Kemp

&

Dr Anne Lagendijk

(co-advisors)

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 validate their predicted roles in skeletal disease using zebrafish knockout models and live imaging to monitor vessel network formation and function.

Statistical genetics

Bioinformatics

Generating zebrafish CRISPR-Cas9 knockouts

High-resolution live imaging
Improving mapping of genetic loci associated with infectious disease in East-Asian ancestry populations Dr Loic Yengo Whole genome sequencing (WGS) has revolutionised our understanding of human biology and population history. To date, the majority of genetic studies have yet been conducted in populations of European ancestry, which biases discoveries of genes influence susceptibility to disease. This project will focus on analysing WGS data generated in 1,000 individuals of Vietnamese ancestry to address various questions relative to genetic diversity (e.g., discovery of population specific haplotypes), disease risk prediction (improvement of polygenic risk scores) and evolution (inference of selection pressure which have shaped the contemporary Vietnamese population). The main application of this project is to quantify the genetic susceptibility to infectious diseases, which is an growing health concern worldwide.

Bioinformatics

Computational biology 

statistical genetics

Integrating genetic risk factors into complex 3D in vitro models to study cellular microenvironment in disease susceptibility

Dr Brett McKinnon

&

Dr Samantha Stehbens

(co-advisors)

The endometrium is a complex tissue that undergoes cyclical regeneration from mesenchymal stem and epithelial progenitor cells. The maturation of these cells into a fully functional endometrium must be tightly regulated. We have identified genetic risk for endometrial related diseases, the functional influence of which, their influence on cellular maturation and the microenvironment are not yet clear. 

We will use complex cell biology and genetic data from patient derived cells to create 3D endometrial models to study the interaction between genetic architecture and cellular microenvironment. We will assess their interaction using single cell and spatial multi-omics data and high end, state of the art quantitative microscopy. This project will link genetics and cell biology in disease susceptibility.

The project will be co-supervised between the Genomics of Reproductive Disorders laboratory and the Laboratory of Dr Samantha Stehbens

Cell biology

Stem cell biology

Genetics

Quantitative microscopy

Single cell genomics

Kidney Spatial Transcriptomics & Genomic underpinnings of Kidney Phenotypes Prof Grant Montgomery TBA TBA
Microenvironmental regulation of melanoma brain metastasis Dr Samantha Stehbens Despite our significant progress, metastatic melanoma remains a highly aggressive, incurable disease, and current therapies, although effective, result in resistance and recurrence. Melanoma tragically kills more 20–39-year-olds than any other single cancer, with one Australian dying every five hours. Melanoma is incredibly invasive- surviving multiple microenvironments to fatally spread to distal organs. Melanoma brain metastases (MBM) occur in up to 75% of patients with advanced disease and are associated with very poor prognosis with near 100% mortality. To date, very few preclinical models exist for MBM, limiting discovery of new drug targets. This project will combine the development of novel preclinical models with live cell microscopy and spatial transcriptomics. We aim to understand the molecular features of MBM, how it survives and spreads in the brain, and the crosstalk of oncogenic signalling with the unique brain microenvironment (vasculature, astrocytes). It will uncover novel druggable pathways, generate new insights to the pathobiology of melanoma to guide the clinical evaluation and introduction of new targeted treatments.

Cancer cell biology

Live-cell microscopy

Spatial transcriptomics

Matrix biology

Neuroscience

Phenotypic landscaping of a bacterial cell Prof Ian Henderson The need to develop rational appraoches to druig design makes matching genes with phenotypes imperative. Using E. coli as proof of principle, this project will combine large-scale chemical genomics to probe growth profiles of bacterial mutants in hundreds of conditions in parallel. By revealiing over 300 million genetic:chemical interactions we will provide a tool to discover leads for gene function and drug action including genes involved in multiple antibiotic resistance and the synergy between antibiotics. Microbial genetics

Genome sequencing

Biochemistry
Prediction of complex traits using genomic data and epigenetic annotations Dr Jian Zeng

Differences between people (like disease susceptibility or height) are complex traits that are determined by genetic variation and measured using genome-wide association studies. This project will study how changes in the genome are linked to individual disease risk with a goal of improving diagnoses using personalised DNA profiles. The project will use genetic data mapping billions of data points that link genetic and epigenetic variation across hundreds of cell types with complex trait biology among hundreds of thousands of individuals that position us with unique opportunities to predict disease susceptibility with precision.

Link: https://cnsgenomics.com

 
Understanding aging at single cell resolution: how organs age differently? Dr Quan Nguyen 

With more than 1 billion people over 60 years old, healthy aging is already a major global challenge. Indeed, 2021-2030 is the United Nations Decade of Healthy Ageing, an initiative between governments to improve quality of human life.

Biological aging, however, is not well understood and significantly deviates from the simple correlation to the number of years a person lives. Even in one body, organs age at different rates. This project will address an extremely exciting question, that is: how organs age differently?

We will investigate aging at single cell resolution and in the context of multiple cell types co-existing within one organ and between multiple organs in the same organism. We will systematically measure the whole transcriptome of single cells in undissociated tissue sections. Bioinformatics approaches will be used to mine this valuable dataset to characterise the aging states of single cells in five organs, brain, liver, spleen, kidney, and heart. We have collected over 150 organs from matched mice in three age groups young vs. middle age vs. old. The student will lead interesting analyses, like comparing cell type compositions, finding changes in gene expression and biological processes, studying proximal and distal cell-cell interaction.

Bioinformatics analyses 

Statistical learning

Genomics technologies

Aging biology

Clinical applications

Using genomics to identify drug repurposing opportunities Dr Sonia Shah This project will be done in collaboration with Prof Glenn King, whose group is exploring the venoms of spiders, centipedes, and scorpions to find novel peptides that can inhibit or activate ion channels. Leveraging association of genetic variation in these ion channels with disease phenotypes, as well as analysis of gene expression signatures from genetic perturbation studies (from Connectivity Map https://www.broadinstitute.org/connectivity-map-cmap), this project aims to identify potential novel therapeutic applications of these venom peptides. Genomic data analysis

Statistical Genetics

Bioinformatics

Contact

Dr Madhavi Maddugoda
Strategic Advisor, Research Training

  m.maddugoda@uq.edu.au


Get notified when the next scholarship round opens