2024 Summer Research Scholarship Program

Project Type: Lab based research

Project Description: Haemostasis is a complex interplay of the vascular endothelium, platelets, and coagulation factors that allows blood to coagulate when necessary. However, the process may lead to thrombosis and obstruction of coronary blood vessels. Individuals with a heightened tendency to form blood clots have an accelerated development of atherosclerosis and are at increased risk of acute coronary syndrome and myocardial infarction (heart attack). Individuals with ischemic heart disease are known to have hyper-reactive platelets that predisposes to thrombosis and adverse cardiovascular events. Understanding the molecular basis of hyper-reactive platelets is necessary for reducing lifetime cardiovascular disease risk and effective application of existing and new anti-platelet drugs. I have identified a new aspect of platelet integrin functioning that may underpin under- and hyper-reactive platelets. This platelet biology is novel, and I lead the international effort to elucidate the implications for platelet function. Should my hypothesis prove to be correct, measurement of this platelet marker in patients will be an informative indicator of thrombotic potential and cardiovascular disease. In this project, we aim to assess the frequency of this covalent integrin in healthy and diseased platelets. We hypothesize that the prevalence of the newly discovered covalent form of platelet integrin conveys functional platelet differences that correlate to platelet reactivity and risk of thrombotic disease. In addition to our differential cysteine alkylation mass spectrometry technique, you will learn how to handle human platelet samples, run SDS-PAGE gels, extract protein, mass spectrometry sample preparation, and analysis. These are highly transferrable skills that benefit any student interested in pursuing molecular biology research.

Lead Supervisor: Professor Phil Hogg

Contact: p.hogg@centenary.org.au

Project Type: Data analysis

Project Description: Mesothelioma is a rare type of lung cancer linked to asbestos exposure. Treating mesothelioma is difficult and there are not many effective therapies. Circulating tumour cells (CTCs) are tumour cells that are released from the primary tumour and travel through the blood. Capturing and analysing these rare cells is now possible using our sensitive liquid biopsy platform, potentially providing an insight into a patient’s cancer. This dry-lab project will involve analysing immunofluorescent images of the patient’s blood slides to identify CTCs from mesothelioma patients.

Lead Supervisor: Dannel Yeo

Contact: d.yeo@centenary.org.au

Project Type: Data analysis

Project Description: Genomics is an essential discipline for scientists aiming to unravel the molecular aetiology of diseases. The past decade has seen rapid advancements in sequencing technology and the generation of vast amounts of genomics data. With the increasing volume of genomics data, the co-development of computational tools and software to store, process, and analyse this data efficiently is essential. One key innovation is the Binary Alignment Map (BAM) file format, which has become the standard for storing sequence alignment data. BAM files contain essential information, including raw sequences, quality scores, genomic coordinates, and alignment quality, which efficient data analysis relies on. Therefore, it is crucial to have tools that can read these files efficiently in popular programming languages like R and Python. Surprisingly, despite their widespread use, no single tool currently exists for efficiently reading BAM files in R. This project will address this knowledge gap by developing an R package capable of reading BAM files in a multi-threaded manner. The package will be built on top of our recently developed C++ engine (ompBAM) for parallel processing of BAM files. The successful implementation of this tool will significantly enhance the speed of downstream genomics analyses, enabling researchers to process large datasets more quickly and efficiently. Applicants for this project should have experience with programming in C/C++ and R. Students will not only learn how to develop an R package, but they will also gain experience in publishing it on R package repositories like CRAN or Bioconductor. Additionally, the proposed package has the potential to be published as a research article, given its necessity and usability.

Lead Supervisor: Dr Chirag Parsania

Contact: c.parsania@centenary.org.au

Project Type: Lab based research

Project Description: Pancreatic cancer is a deadly disease with a 5-year survival rate of less than 12%. There are limited effective therapies. Targeted therapies, which target specific targets/pathways, are now being tested in the clinic. However, identifying patients that would benefit from targeted therapies is difficult. Our lab has generated several 3D organoid models from patient’s tumour tissue. This project will test several promising targeted therapies using our patient-derived organoid models and examine the expression of specific targets/pathways. This project will suit students interested in cancer and cancer therapies who have a background in cell biology or pharmacology.

Lead Supervisor: Dannel Yeo

Contact: d.yeo@centenary.org.au

Project Type: Lab based research

Project Description: Cystic fibrosis (CF) is the most common rare genetic disease worldwide affecting 1 in 3000 births. This disease occurs due to mutations in the CFTR gene, causing impaired chloride transport, thickening of the mucus in the lungs and the gastrointestinal tract, and also causes chronic lung inflammation and immune dysfunction. The combination of these host factors creates an ideal niche for opportunistic infections, and therefore predisposes CF patients to chronic and often terminal lung infections. Mycobacterium abscessus (Mabs) is an emerging opportunistic pathogen of global concern, largely due to high antimicrobial susceptibility with very few available treatments currently available. CF patients are at increased risk of Mabs infections, however there is an incomplete understanding of the host-pathogen interface underpinning infection. To identify and develop new therapies to treat or prevent Mabs infection in CF patients, we need to understand the pathways that the bacteria uses to cause infection. The aim of this project is to investigate whether Mabs clinical isolates adopt a hypervirulent phenotype under CF conditions, and to understand how the bacteria is able to manipulate the host landscape to cause infection in CF patients.

Lead Supervisor: Dr Matt Johansen

Contact: m.johansen@centenary.org.au

Project Type: Lab based research

Project Description: Gene therapy holds the promise of curing diverse genetic diseases. However, constant delivery of a therapeutic gene is often not ideal. This project will contribute to our efforts to develop improved transcriptional regulators for controlling the timing and dose of therapeutic genes. You will learn and apply molecular and cellular biology to increase the safety and efficacy of next-generation gene therapies.

Lead Supervisor: Associate Professor Dan Hesselson

Contact: d.hesselson@centenary.org.au

Project Type: Lab based research

Project Description: Adeno-associated virus (AAV) is widely used as a gene therapy vector due to its tissue-tropism and safety profile. Improved transduction efficiency of AAV vectors has been achieved by engineering capsids with higher affinity, cell specificity and increased resistance to neutralising antibodies. Increasing AAV-mediated therapeutic efficacy by modulating host entry factors remains unexplored. KIAA0319L (aka AAV receptor (AAVR)) is an essential host entry factor for most AAV serotypes. We have identified other factors dependent and independent of KIAA0319L that also regulate AAV uptake. Molecular genetic and cell biological techniques will be used to examine AAV uptake when host factor expression is modulated. Protein sequences within AAVR which affect trafficking and localisation will also be examined for how they influence AAV uptake. Priority will be given to students considering undertaking SoMS Honours in 2025. Techniques: DNA cloning, cell culture, Western blotting, CRISPR/Cas9, virus transductions, RNA-Seq, co-immunoprecipitation, mass spectrometry, flow cytometry, confocal microscopy

Lead Supervisor: Dr Chuck Bailey

Contact: c.bailey@centenary.org.au

Project Type: Lab based research

Project Description: Alternative splicing (AS) generates multiple protein isoforms from almost every gene – each with potentially different biological functions. However, the mechanism by which RNA binding proteins (RBPs) contribute to this diversity remains relatively unexplored. We have uncovered a new evolutionarily-conserved mechanism by which functional protein diversity is conferred by RBP-mediated ‘switching’ at tandem alternative splice sites. This project provides a real opportunity to fill the significant knowledge gap concerning these additional AS mechanisms and their biological consequences. We have identified a novel spliceosomal protein and its remarkable specificity in directing splice site fidelity at tandem donor sites. We found that mice deficient for this RBP are embryonic lethal with severe morphological defects during embryogenesis. While out-of-frame A5′SS usage with nonsense-mediated decay (NMD) pervades, small in-frame protein variations, we refer to as ‘molecular micro-switches’, occur in ~20% of events. We have subsequently identified new micro-switches in the functional domains of many developmentally important proteins. This project will examine the biochemical and structural bases for alternative splicing regulation by this RBP. Additionally, project can be configured for a wet-lab project or for bioinformatics analysis only. Techniques: DNA cloning, cell culture, Western blotting, CRISPR/Cas9, virus transductions, flow cytometry, recombinant protein production, bioinformatics (R-based programming and data visualisation).

Lead Supervisor: Dr Chuck Bailey

Contact: c.bailey@centenary.org.au

Project Type: Lab based research

Project Description: Background: Men are more than twice as likely to die from melanoma compared to women. Although several explanations have been proposed for this phenomenon, the puzzle remains incomplete. This project provides an alternative theory that differences in genes located on sex chromosome may explain differences in the ability to combat cancer between males and females. The Project: We have identified several epigenetic regulators on the X chromosomes that can escape from inactivation and are expressed at higher levels in women than in men. In addition, the loss of Y chromosomes in males may contribute to a poorer prognosis. However, the precise mechanisms by which these factors might either protect females from or worsen cancer in males are not yet fully understood. The successful candidate will investigate how changes in the expression of genes encoding these regulators in melanoma cells could contribute to more severe disease outcomes in males compared to females.

Lead Supervisor: Dr Jessamy Tiffen

Contact: j.tiffen@centenary.org.au

Project Type: Lab based research

Project Description: To develop new subunit tuberculosis vaccines we need to better understand how adjuvants trigger innate immune cells. This project will examine the early interactions between new adjuvants and cells of the innate immune response.

Lead Supervisor: Professor Angelo Izzo

Contact: a.izzo@centenary.org.au