Summer Research Program - IMB
New chemical space as a source of new drug leads
Supervisor: Dr Zeinab Khalil (z.khalil@uq.edu.au)
Duration: 10 weeks
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.
Investigating a possible causal relationship between left-handedness, disease and mortality using Mendelian randomisation
Supervisor: Professor David Evans (d.evans1@uq.edu.au)
Duration: 10 weeks
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. The prevalence of left-handedness in modern western cultures is approximately 9% and is greater in males than females. 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 possible causal relationships between handedness and a variety of life outcomes including mortality and common complex diseases using a statistical genetics technique called Mendelian randomization.
Expected outcomes and deliverables: Scholars will have an opportunity to work in a research group, gain skills in data analysis and generate a publication from their research.
Location: Institute for Molecular Bioscience
Suitable for: The student should be familiar with the software R and have knowledge of human genetics and statistics.
A Mendelian Randomization Analysis to investigate the possible causal relationship between a woman’s years ovulating and ovarian cancer
Supervisor: Dr Gunn-Helen Moen (g.moen@uq.edu.au)
Duration: 10 weeks
Ovarian cancer has the worst prognosis of the common female cancers. It is well established from observational studies that both a woman’s life-time use of oral contraceptives and her number of pregnancies are associated with a strong decreased risk of ovarian cancer. This information can be put together in a variable “years ovulating”, which is calculated as: years menstruating - years on the oral contraceptive pill - 0.75 * (live births + stillbirths).
Observational studies are prone to confounding and conclusions regarding causality cannot easily be drawn. Mendelian randomization (MR) is a method that uses genetic data to provide information on causality in observational studies. We will use MR to explore if number of years ovulating is causal for ovarian cancer risk.
Expected outcomes and deliverables: Scholars will have an opportunity to work in a research group, gain skills in data analysis and generate publications from their research.
Location: Institute for Molecular Bioscience
Suitable for: The student should be familiar with the software R. It would also be preferred if the student have some background or interest in bioinformatics, genetics or epidemiology.
Discovery and characterisation of novel organoselenium compounds as a new class of antimicrobial agents
Supervisors: Louise Friberg (day-to-day), Dr Karl Hansford (primary) (k.hansford@imb.uq.edu.au)
Duration: 10 weeks
Antibiotics save lives and enable modern medicine. But as pathogenic microbes continue to evolve and evade the effective mechanisms of current antibiotics, new antimicrobial agents are urgently needed.
Our group has developed novel organoselenium compounds with activity against various strains of resistant microbes. We now have an opportunity to further our understanding of these compounds by investigating the structure-activity and structure-toxicity relationships of this class of compounds.
As a student, you now have the unique opening to join us to be a part of the discovery of a novel chemotype to fight superbugs!
Expected outcomes: The student will have the opportunity to understand the unique challenges of antibiotic discovery and development in a globally recognised research group, and contribute to a high impact research area. The student will have a clear set objectives and will receive continual guidance during the course of the project.
The project will provide experience with organic synthesis in a laboratory setting, including solid and/or solution phase synthesis techniques and typical purification/analytical methods such as HPLC, flash column chromatography, LCMS, NMR, TLC etc. Target compounds will be will be tested for antimicrobial activity.
Suitable for: Open to applications from students with an interest in drug discovery, with a background in chemistry. Synthetic organic chemistry skills are required, and the student must have completed CHEM2054.
Other important details: Interested students are to contact the supervisor/s prior to submitting an application.
Developing a molecular toolkit for investigating the Commander trafficking machinery.
Supervisor: Dr Michael Healy (m.healy@imb.uq.edu.au)
Duration: 10 weeks
The Commander complex is a conserved regulator of intracellular trafficking. This ancient complex consists of 15 core components as well as a number of associated proteins that can be subdivided into three (3) categories: the COMMD/Coiled coil domain containing proteins, the Retriever complex (a distant relative of the Retromer complex) and a number of associated proteins. Functionally Commander couples to Sorting Nexin 17 (SNX17) to facilitate the recycling of over 100 cell surface proteins including key receptors such as, LDLR, LRP1, p-Selectin and the amyloid precursor protein. In addition, Commander dysfunction has been linked to various disease pathologies including X-linked intellectual disability. It is therefore crucial to understand the structure, mechanism and function of this complex, an understanding that has remain largely elusive to date.
The specific aim of this project is to act in a complementary fashion to a larger project. The aims of larger project are to resolve a high resolution structure of the 16 subunit Commander complex, both by single particle analysis of the isolated complex and analysis of the structure of the complex in-vivo using correlative light electron microscopy. However, before we can achieve this we will need to characterise a set of molecular tools generated during my PhD, this will be the focus of the proposed project.
Aim 1: Resolve a high-resolution crystal structure of the N-terminal domain of Commd7 bound to Nanobody D12
Nanobodies are small, soluble, high affinity molecules, that can be used in a wide array of tasks including, in cell imaging, and complex purification. In previous unpublished work done in collaboration with A/Prof. Wai-Hong Tham (WEHI ) a high affinity nanobody was developed against a stable tetrameric subset of the Commd proteins (Commd-5-7-9-10). After some initial mapping experiments by ITC this nanobody (Nb D12) was found to bind selectively to the helical n-terminal domain of Commd7. However, the exact binding site/orientation of this molecule is unknown. Given this has the potential to disrupt the structure of the overall complex it is critical that we gain a better understanding of this interaction before proceeding to use this Nb to isolate the 16 subunit Commander complex. While various biochemical and cellular techniques will be performed in tandem the gold standard for assessing this interaction will be to obtain a high-resolution structure of Nb D12 bound to the HN domain of Commd7.
Aim 2: Map the binding site of several macrocyclic peptides and resolve a high-resolution structure.
Likewise in Aim 2 we will endeavour to better understand the interaction between a semi-stable hexamer (Commd1-2-3-4-6-8) and a series of macrocyclic peptides that were developed in collaboration with Dr. Toby Passioura (University of Sydney). Currently this project is less developed and so initial experiments will focus on mapping the interaction site to a particular Commd or interface with a subsequent goal been to produce a high resolution crystal structure.
Developing peptide-based antimalarial drugs
Supervisor: Dr Nicole Lawrence (n.lawrence@imb.uq.edu.au)
Duration: 10 weeks
Host defence peptides can selectively recognise and kill pathogens, while leaving healthy cells unharmed. We are developing new peptide-based medicines for treating malaria that are safe and selective, and also are less likely to result in malaria parasites developing drug resistance. Design and validation of new drug candidates requires pre-screening for desirable characteristics prior to testing for antimalarial activity using in vitro assays and eventually animal studies.
The summer research scholar will contribute to producing and validating some of the next generation of antimalarial peptides.
Zebrafish as a model to understand human diseases
Supervisors: Prof Robert Parton (r.parton@imb.uq.edu.au) and Dr Harriet Lo
Duration: 10 weeks
Our group focuses on the cell surface or plasma membrane, the interface between the cell and its outside environment. Our work aims to understand how specialised plasma membrane domains, termed caveolae, are able to respond to stresses by sending a signal into the cell. The disruption or loss of caveolae is linked to numerous human diseases, including muscular dystrophy and lipodystrophy. We use the fast-developing zebrafish embryo to model human disease to help us to discover how systems are affected by disease.
Students will have the opportunity to be involved in the live imaging of fluorescent zebrafish, use of state-of-the-art genetic technology, generation of transgenic zebrafish lines, as well as gain skills in data collection and analysis.
Regulation of liver protein secretion and its regulation by circadian and feeding rhythms
Supervisor: Associate Professor Frederic Gachon (f.gachon@imb.uq.edu.au)
Duration: 10 weeks
While most of blood proteins are secreted by the liver, how they are secreted is still not clear, as well as the regulation of this secretion. Our previous experiments showed that liver protein secretion is rhythmic and regulated by feeding rhythms in both mouse and human. Using newly generated animal model and experiments in cultured cells, this project will decipher the mechanisms involved and the consequences of the perturbation of this rhythmic secretion on animal physiology.
Impact of light and circadian rhythms on the embryonic development of the zebra finch
Supervisor: Associate Professor Frederic Gachon (f.gachon@imb.uq.edu.au)
Duration: 10 weeks
The circadian clock orchestrates virtually all aspects of physiology so that organisms may better anticipate predictable daily changes caused by the Earth’s rotation. Consequently, disruption of circadian rhythms, or chronodisruption, is associated with several pathological or psychological conditions. Nevertheless, most research has focussed on nocturnal rodents, with little information on diurnal animals. This project proposes to study the impact of chronodisruption on the physiology of a diurnal animal: the common Australian zebra finch (Taeniopygia guttata). In collaboration with Prof. Kate Buchanan (Deakin University), we will study the impact of light and circadian rhythms on the embryonic development of the zebra finch, opening new perspective about the impact of the environment on the development of birds.
Investigating blood vessel formation and function
Supervisor: Dr Emma Gordan (e.gordon@imb.uq.edu.au)
Duration: 10 weeks
The research within our lab is focused on the formation and maintenance of the blood vascular system. Vessels form complex branched networks that supply oxygen and nutrients to all body tissues. The signals controlling blood vessel expansion, identity and migration are all downstream of a single, common complex at the cell surface, yet exactly how this diverse range of functions is differentially regulated, depending on the physiological need, remains unknown.
The specific focus of our research is to determine the precise molecular signals that control endothelial cell interactions within the vessel wall and the surrounding environment. Dysregulated control of these processes contributes to the progression of a wide range of human diseases, including cancer growth and metastasis, diabetic eye disease, stroke and atherosclerosis.
Students will have the opportunity to be involved in live imaging of cells isolated from blood vessels and analysing how genetic mutations affect cell behaviour, in addition to gaining experience in data collection and analysis.
Using transcriptomic data to understand the mechanisms of Motor Neurone Disease
Supervisor: Dr Fleur Garton (f.garton@imb.uq.edu.au)
Duration: 8 weeks
This project aims to investigate whether this phenomenon may be occurring in other MND risk loci. The UNC13A splicing event has been shown to occur due to mislocalisation of TDP-43 (an important regulator of RNA-splicing). UNC13A is not the only gene targeted by TDP-43 and we know of at least one other gene in a MND genetic risk locus, that may also be affected by TDP-43 mislocalisation.
By leveraging off these recent discoveries in the field, this project aims to further explore cryptic exon splicing as a mechanism of MND. Computational integration of genetic and transcript data will be required. It will involve the use of in-house (human muscle) and publicly available (human iPSC- derived motor neurons) transcriptome data (RNA-seq) to look for evidence of cryptic splicing events in MND cases and controls.
The overall aim of this project is to identify genetic links with the molecular mechanisms associated with MND. The long-term goal of this research is to use this detailed understanding of genetic risk of MND to help define novel therapeutic avenues.
Expected outcomes: Applicants can expect to gain experience and knowledge in QC and processing of transcriptomic (RNA-seq) data, together with genetic data. Students may also be asked to produce a report or oral presentation at the end of their project.
Suitable for: This project is open to applications from students with a strong interest in molecular genetics, genetic and genomics, year 3 undergraduate and postgraduate students.
Other important details: Interested students must contact the supervisor/s, prior to submitting an application. Evidence of supervisor support is required to be uploaded as part of the application process. Students are also welcome to contact the supervisor if they are
interested in a related project area.
Drug development for chronic diseases using next-generation protein micro-scaffolds
Supervisors: Professor David Craik (d.craik@imb.uq.edu.au) and Dr Conan Wang (c.wang@imb.uq.edu.au)
Duration: 10 weeks
Scientific development of drugs is essential for alleviating the burden of chronic diseases to society and improving the wellbeing of patients and their families. This project involves the development of targeted approaches for design of new drugs using protein micro-scaffolds that have the benefit of reduced off-target effects and improved safety and activity compared to traditional drugs. All major pharmaceutical companies are activity pursuing these types of drugs. In this project, training opportunities are available in cutting-edge methodologies for drug design now used in leading academic and industrial laboratories, such as computational prediction, in vitro biological evolution, and chemical late-stage modification to improve drug activity and efficacy. These methods will be applied to design new drugs against cancer, cardiovascular disease, or drug-resistant bacterial infection. The hope is to design new and better drugs for human health.
Phenome-wide association analysis of the genetically predisposed supertaster status
Supervisor: Dr Daniel Hwang (d.hwang@uq.edu.au)
Duration: 10 weeks
Taste perception plays a critical role in food preference and intake and thus having a long-term impact on health. It has been extensively studied that human taste responses to the bitter substance phenylthiocarbamide (PTC) and its structurally related chemical propylthiouracil (PROP) vary greatly between individuals. Approximately 30% of the population find these bitter chemicals tasteless and are often referred as non-tasters; the remaining 70% find them extremely bitter and are referred as tasters or supertasters. An individual’s “supertaster status” is primarily determined by the genetic variation in the bitter taste receptor gene TAS2R38 that accounts for approximately half of the variance in taste response to PTC and PROP.
Being a supertaster or not has been associated with phenotypes other than taste perception. For example, supertasters have a lower preference for dark green vegetables, in particular cruciferous vegetables such as Brussel sprouts, because they find these vegetables more bitter than non-tasters. Furthermore, supertasters tend to drink less alcohol and coffee and are less likely to be a smoker. Recent studies showed that the TAS2R38 bitter taste receptor is expressed in epithelial cells in the airway and the TAS2R38 genotype is associated with immune response to upper respiratory infection. This finding revealed the health impact of supertaster status beyond taste perception.
With the continuously increasing number of genome-wide association studies (GWAS) in humans, it is possible to assess the influence of supertaster status across the whole human phenome by examining the association with the TAS2R38 genotype in these GWAS results. As an exploratory study, we will use multiple online tools, including our own Complex-Trait Genome Virtual Lab (CTG-VL; https://genoma.io/), to assess the genetic association between the TAS2R38 genotype and > 1000 health and disease outcomes in publicly available GWAS results. The outcome will provide new insights into the health impact of the genetically predisposed supertaster status.
Expected outcomes: Scholars would gain knowledge in the biology and genetics of taste perception, learn how to conduct genetic analyses using existing online resource, and have an opportunity to generate a publication from their research.
How do the aging process occur in the brain at a single cell resolution?
Supervisor: Dr Quan Nguyen (quan.nguyen@imb.uq.edu.au)
Duration: 10 weeks
Description: The brain is such a complex organ that each of the many brain regions controls a distinct set of cognitive functions. Understanding of the variations between these regions at cell and gene levels is lacking. Recent genome-wide association studies (GWAS) of brain MRI images from large biobanks and consortia for >50,000 people have suggested hundreds of genes contributing to differences in areas of cortical brain regions. This opens an unprecedented opportunity to link genetic data to changes in brain morphologies across individuals in time (lifespan) and space (brain regions). However, activities of GWAS genes in each cell type in these MRI-defined regions are largely unknown. Further, little understanding exists on the roles of non-neuronal cells in the brain, i.e., glia, which make up more than half of all brain cells. Throughout life, glial cells maintain the wellbeing of neurons and are key for healthy brain aging but are also involved in various brain disorders like stroke, epilepsy, and Alzheimer’s diseases. This project aim at investigating how genetic variants associated with brain regions manifest their effects differently across genes and cells in space (brain regions) and time (young vs aged). Cutting-edge data are readily available for the student to analyse cell types and compare differences between young and old brain samples.
Expected outcomes and deliverables: Students would learn skills in big biological data analysis. There are opportunities for presenting at conferences and co-authored publications.
Suitable for: This project is open to applications from students with good analytical skills. Familiarity to R and/or Python scripting is required.
Improvement of water quality by applying silver products
Supervisor: Dr Zyta Ziora (z.ziora@imb.uq.edu.au)
Duration: 10 weeks
Background: Growing industrialization and various other human activities have led to the reducing of clean water resources. The ever-increasing demand for hygienic water has prompted the development of technologies that can be used for treating polluted water. Many water-borne diseases are a result of blooming microbial populations in water. Over the years, conventional methods for water purification that prevent microbial growth, such as chlorination, ozonation etc., have limitations owing to the formation of disinfection by-products which are carcinogenic in nature. It is therefore vital to develop effective and low-cost technologies that address the problem.
Hypothesis: Various silver products can be applied and use as an antimicrobial agent to improve the water quality.
Aim: To identify an effective concentration of silver ion solutions against common microbes in wastewater.
Approach: A model consisting of artificial sweat mixture liquid and sterile water will be used for sampling of three common wastewater bacteria, P. aeruginosa, E. coli, and S. aureus, fungi Candida Albicans, and biofilms. Samples will be collected immediately after the addition of silver, and 2, 4, and 24 hours afterwards.
This study will demonstrate the practical use of silver ions as potential disinfection agents in managing water quality.
Expected outcomes and deliverables: The applicant is expected to produce a report and give an oral presentation.
There is a possibility to continue this research as a PhD study in the joint project with the industry.
The generated results from this research can be included in the planned publication in the reputable peer review journal.
Suitable for: This project is open to applications from students with a background in chemistry, inorganic chemistry, and microbiology, 3-4-year students.
Ancestry classification of mixed ancestry individuals in the UK Biobank
Supervisors: Dr Kathryn Kemper (k.kemper@imb.uq.edu.au) & Dr Loic Yengo (l.yengo@imb.uq.edu.au)
Duration: 10 weeks
To date, the majority of human genetics studies have been conducted in individuals of European ancestry, although European ancestry only constitutes 16% of the global population. Therefore, there is a real need to improve our understanding of the genetic determinants of human traits in individuals with non-European ancestries, and also in people with mixed ancestry backgrounds.
This project aims to describe and classify the genomes of a cohort of about 2000 individuals from the UK with self-reported ‘mixed’ ancestry. There are two main tasks are to be completed using publicly available programs such as STRUCTURE (Pritchard et al. 2001 Genetics 155(2):945).
The tasks are to:
1. Describe and define the genomic ancestry profile of ‘mixed’ ancestry individuals.
2. Assign genomic regions of ‘mixed’ ancestry individuals to the ancestries identified in (1) .
Students will gain skills in the analysis of human genomic data, and working in a HPC environment. Students will be required to comply with human ethics requirements.
The project will conclude with a brief report to project supervisors and a presentation to the group.
The project is suitable for students wanting to gain experience in computational biology and genome analysis. It is open to any students with an interest in the topic. Helpful background knowledge may include genetics and/or statistics.
The student will be part of the PCTG (https://cnsgenomics.com/), within the Institute for Molecular Bioscience at the St Lucia campus. The PCTG is a group of around 40 researchers and PhD students. The student will have opportunity to attend seminars and other activities within the PTCG.
Computational analysis and design of HDAC7 inhibitors towards new inflammatory drugs
Supervisors: Dr Huy Hoang (h.hoang@imb.uq.edu.au), Dr Jeffrey Mak (j.mak@imb.uq.edu.au), and Professor David Fairlie (d.fairlie@imb.uq.edu.au)
Duration: 8 weeks
The histone deacetylase HDAC7 is an emerging anti-inflammatory drug target, but there remains a lack of selective inhibitors. The student will use molecular docking and molecular dynamics simulations to study the structural basis of the selectivity of our best-in-class HDAC7 inhibitors, and then design new HDAC7 compounds in silico.
Synthesis of protein degraders with state-of-the-art exit vectors
Supervisors: Dr Timothy Hill (t.hill@imb.uq.edu.au), Dr Jeffrey Mak (j.mak@imb.uq.edu.au), and Professor David Fairlie (d.fairlie@imb.uq.edu.au)
Duration: 8 weeks
PROTACs are compounds that use specialised motifs to mediate target protein degradation, but the linkage points (exit vectors) for such motifs require strategic positioning. In this project, the student will synthesise new PROTACs with state-of-the-art exit vectors towards new anti-inflammatory drugs.