2022 SBSP BACHELOR OF BIOMEDICAL SCIENCES HONOURS PROJECT

2022 SBSP BACHELOR OF BIOMEDICAL SCIENCES HONOURS PROJECT

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PROJECT DETAILS

A) Project Title: Investigating molecular mechanisms of a diet and resistance exercise program to prevent sarcopenia

in the elderly.

B) Supervisory Details:

Primary Supervisor Name: Professor Lisa Wood

Location: HMRI, Level 2 – West / Room 606, Medical Sciences Building

Email: [email protected]

Phone: 49217485

Co-Supervisor Name: Dr Evan Williams

Location: HMRI, Level 2 – West


Phone: (02) 404 20910

Co-Supervisor Name: Dr Hayley Scott



Phone: (02) 4042 0113

C) Background and Summary of Proposed Research, including a clear hypothesis, aims and experimental approach:

The loss of muscle mass, strength and function as we age (sarcopenia) is associated with increased risk of falls, hospitalisation and reduced independence. Sarcopenia is a common comorbidity of arthritis and osteoporosis, all of which can accelerate age-related functional decline. We recently completed a randomised controlled trial investigating whether improving nutrition and home-based resistance training in older untrained adults during a 16 week period can improve outcomes such as muscle mass, bone density, grip strength and gait speed. This project will investigate the molecular pathways modulated by the intervention using Affymetrix Microarray (Clariom S) to measure peripheral blood gene expression. Bioinformatics tools will be used for network and pathway analysis. The student will develop unique experience in molecular biology laboratory techniques and bioinformatics tools used in gene profiling.

HYPOTHESIS: Improvements in muscle mass, bone mineral content, muscle strength and function following a 16-week

combined exercise and nutrition intervention in adults at risk of sarcopenia, are associated with differential gene expression

of immune and metabolic pathways.

AIMS: To use transcriptome and network analysis to identify changes in immune and metabolic pathways following a 16-

week combined exercise and nutrition intervention in adults at risk of sarcopenia, and to examine the relationship between

these changes and improvements in muscle mass, bone mineral content, muscle strength and function.

METHOD: This study will utilise previously collected microarray data from an RCT in adults at risk of sarcopenia. They will perform transcriptome analysis using microarray data, gene ontology and pathways analysis using computer programs. The student will then confirm these findings in the lab by performing qPCR for gene expression and Enzyme-linked Immunoassay (ELISA) to confirm protein expression.

Laboratory and statistical techniques: Microarray data will be analysed using R studio. Relationships of gene expression profiles will be examined using hierarchical clustering. Potential molecular mechanisms will be investigated by both gene ontology and pathways analysis using STRING (Search Tool for the Retrieval of Interacting Genes/Proteins), GATHER (Gene Annotation Tool to Help Explain Relationships) and KEGG (Kyoto Encyclopedia of Genes and Genomes). These findings will then be pursued in the lab by measuring gene expression by qPCR and protein expression by ELISA. Associations between clinical improvements and changes in molecular pathways will be examined using multiple regression.

D) Laboratory Location

Wood Lab: HMRI, Level 2 – West Wing


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PROJECT DETAILS Project Title: Promoting oligodendrocyte maturation in the preterm neonatal brain

A) Supervisory Details:

Primary Supervisor Name: Jon Hirst

Location: Level 3 East HMRI


Phone: mob 0413961638

Co-Supervisor Name: Julia Shaw



Phone: 02 4042 0485

Co-Supervisor Name: Hannah Palliser



Phone: 02 4042 0371

B) Background and Summary of Proposed Research, including a clear hypothesis, aims and

experimental approach:

Preterm birth can have serious effects on the neurodevelopment of the offspring with white

matter development particularly affected. Behavioural disorders such as attention deficit

hyperactivity disorder (ADHD) and anxiety are also relatively common in children who were

born preterm and may be linked to white matter deficits. We have found that early loss of key

steroids from the placenta may be a causative factor as steroid-GABAA receptor interactions

directly stimulate proper neurodevelopment through their promotion of oligodendrocyte

maturation. Therefore, we propose that targeting the GABAA receptor may be an effective

approach to improving white matter development and behaviour following preterm birth. We

have used our unique guinea pig model of preterm birth to administer GABAA receptor

agonists and steroid-producing compounds for one week following birth. This project will

focus on evaluating the possible benefits these therapies have in stimulating white matter in

the postnatal brain, in addition to the steroid producing capacity and drug metabolising ability

of the neonate. We hypothesise that these therapies will increase the maturation of

oligodendrocytes in the early postnatal period and return myelination to normal and

improved childhood behaviour. To determine the effect of postnatal administration of our

novel treatments on oligodendrocyte maturation fixed tissue will be used for

immunohistochemical analysis of the oligodendrocyte lineage, as well as GABAergic

interneurons and markers of cell death. Overall, this project will identify a clinically feasible

therapy to improve outcomes for vulnerable newborn infants.

C) Laboratory Location: Level 3 East HMRI


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PROJECT DETAILS

A) Project Title: Discovering and developing novel cardioprotective therapies to mitigate cardiovascular

complications of cancer therapies


Primary Supervisor Name: A/Prof Doan Ngo

Location: Hunter Medical Research Institute


Phone: 0240339386

Co-Supervisor Name: Dr. Tatt Jhong Haw



Phone: N/A

Co-Supervisor Name (must be completed): A/Prof Aaron Sverdlov


Phone: 0240420725

C) Background and Summary of Proposed Research, including a clear hypothesis, aims and experimental

approach:

Cancer survival rate has greatly improved in the last two decades due to the emergence of next-generation anti-

cancer agents. However, some anti-cancer treatments unexpectedly caused cardiotoxicity and led to

cardiovascular adverse events (e.g., heart failure/sudden cardiac arrest). This has led to early disruption or

discontinuation of potentially life-saving anti-cancer therapy that can be detrimental to patients’ health, quality,

of life and survival. Therefore, there is an urgent need to identify novel cardioprotective therapies to mitigate

cardiotoxicity whilst preserving the effectiveness of current anti-cancer therapies.

We propose an exciting pilot study to identify novel cardioprotective drugs from of a library of preclinical/clinical

drugs by high-throughput screening. We will screen and identify pre-clinical and clinical compounds with

cardioprotective effects that protect cardiac cells from cardiotoxic chemotherapies. We hypothesised that some

pre-clinical and clinical drugs may have previously unreported beneficial cardioprotective effects that may

prevent cancer therapies-induced cardiotoxicity. The main aims of this project are to 1) screen and identify

potentially novel cardioprotective agents from pre-clinical and clinical drugs; and 2) elucidate the underlying

mechanism(s) and targets for future drug discovery. Experimental approach:

Aim 1: A dose response study will be performed with a preclinical/clinical compounds library (up to 700) to

screen for novel cardioprotective compound(s). Each compound will be tested for their potential to protect

cardiac cells from cardiotoxicity induced by chemotherapies (e.g. doxorubicin, carfilzomib). Cardiotoxicity will be

assessed in terms of cell viability at three timepoints (24, 48 and 72 hrs) using the Cell-Titre GloTM assays.

Aim 2: The study will be repeated based on the best candidate drug, dose, and timepoint determined at Aim 1.

Cell lysates will be collected for RNA and protein isolation. The expression levels of mRNA and protein targets

associated with cardiotoxicity (e.g. DNA damage, oxidative stress, and mitochondrial dysfunction) will be

assessed by qPCR and/or immunoblot assays.

D) Laboratory Location:

Hunter Medical Research Institute, Level 3 East

Cardiometabolic/Cardio-oncology Research Group

mailto:[email protected]




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PROJECT DETAILS

A) Project Title: Molecular investigation of immune pathways in children with asthma using novel bioinformatic

tools


Primary Supervisor Name: Dr Bronwyn Berthon



Phone: 40420116

Co-Supervisor Name: Professor Lisa Wood

Location: HMRI, Level 2 – West / Room 606, Medical Sciences Building


Phone: 49217485

Co-Supervisor Name: Dr Evan Williams



Phone: (02) 404 20910


approach:

We have successfully completed a 6-month randomised controlled trial (RCT) to improve diet quality in children with asthma. Following intervention, lung function improved and the number of children who had multiple asthma attacks in a 6-month period declined. It is hypothesised that the positive results seen in this trial may have been mediated by changes in the immune system.

This project is a molecular investigation into immune pathways modulated by our intervention, including gene expression analysis of peripheral blood mononuclear cell samples using Nanostring and associated bioinformatics tools to complete network and pathway analysis. The student will develop unique experience in molecular biology laboratory techniques and bioinformatics tools used in gene profiling.

HYPOTHESIS: Improvements in lung function and reduced asthma-related illness following a dietary intervention are

associated with differential expression of immune system pathways.

AIMS: To use transcriptome and network analysis to identify changes in immune pathways following a dietary intervention

in children with asthma, and to examine the relationship between these changes and improvements in lung function and

exacerbation frequency.

METHOD: This study will utilise stored peripheral blood mononuclear cell (PBMC) samples previously collected during an RCT in children with asthma. The student will perform the RNA extractions, transcriptome analysis using Nanostring assays, and gene ontology and pathways analysis using computer programs.

Laboratory and statistical techniques: RNA will be extracted from PBMCs using the RNeasy Mini Kit (Qiagen, Hilden, Germany), quantitated using the Quant-iT RiboGreen RNA Assay Kit (Molecular Probes Inc, Invitrogen, Eugene, OR, USA). PBMC transcriptome analysis will be performed in baseline and 6-month samples using the Nanostring nCounter Analysis System Human Immunology v2 Panel (Nanostring Technologies, Seattle, WA, USA), where expression of 579 immunology-related genes and 15 internal reference controls will be measured. Nanostring data will be analysed using nSolver Analysis Software v2.5 (Nanostring Technologies). Gene profiles will be analysed for differential expression by paired t-test for significance. Relationships of gene expression profiles will be examined using hierarchical clustering. Potential molecular mechanisms will be investigated by both gene ontology and pathways analysis using STRING (Search Tool for the Retrieval of Interacting Genes/Proteins), GATHER (Gene Annotation Tool to Help Explain Relationships) and KEGG (Kyoto Encyclopedia of Genes and Genomes). Associations between clinical improvements and changes in inflammatory pathways will be examined using multiple regression.

D) Laboratory Location: Wood Lab: HMRI, Level 2 – West Wing


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PROJECT DETAILS

A) Project Title: TLR2-induced type III IFN-lambda control of respiratory virus infection by

human airway epithelial cells

B) Supervisory Details :

Primary Supervisor Name: Nathan Bartlett

Location: HMRI – Level 2 East/West


Phone:x20171

Co-Supervisor Name: Jason Girkin

Location: HMRI


Phone: x20847

C) Background and Summary of Proposed Research, including a clear hypothesis, aims and


Innate immune control of viruses at the respiratory mucosal surface is a key determinant of disease

outcome. We have discovered that toll-like receptor (TLR2) can be stimulated to prime airway

mucosal immunity and boost responses to respiratory viruses including rhinovirus and coronavirus.

Transcription factor NF-κB activation and induction of type III interferons (IFN-λs) is associated with

TLR2-stimulation mediated anti-viral immune boosted response however a direct role for IFN-λ has

not been demonstrated. This project will test the hypothesis that TLR-2 induced IFN-λ production

during rhinovirus and coronavirus infection requires NF-κB activation and induces expression of

interferon stimulated genes (ISG). The project Aims to use pharmacological intervention of NF-κB

and antibody blocking of the IFN-λ in virus-infected primary human airway epithelial cells (AECs) to

define the role of these molecules in TLR2-boosted IFN and ISGs expression and control of virus

infection.

Primary human AECs will be differentiated at air-liquid interface, infected with either coronavirus of

rhinovirus and treated with NF-κB inhibitor (IKK inhibitor BMS345541) and or/IFNLR1 blocking

antibody. NF-κB (p65) and IFN-λ induced STAT1 phosphorylation will be assessed by western blot.

Viral load – qPCR and TCID infectivity assay; ISG expression measured by qPCR and interferons (type

I and type III)/inflammatory cytokines measured by Legendplex protein measurement platform.

Expected outcomes – this project will define the innate immune signalling pathway operating in

virus infected human airway epithelial cells induced by TLR2 stimulation, mediated by NF-κB-

regulated type III IFN expression and induction anti-viral immunity.


HMRI


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PROJECT DETAILS

A) Project Title: A biosensor for stroke. Developing a novel organoelectronic device to detect D-serine in saliva

B) Supervisory Details

Primary Co-Supervisor Name: Alan Brichta

Location: MSB309B

Email: Alan Brichta

Phone: 4921-7026

Primary Co-Supervisor Name: Paul Dastoor

Location: P-123


Phone: 1-5426

Co-Supervisor Name: Fatima Shad Kaneez

Location: University of Technology Sydney



approach:

Background and Summary

Stroke is the second most common cause of death and the third common reason for disability worldwide [1]. NMDA (N-

methyl-d-aspartate) receptors (NMDARs) play a central role in the aetiology of ischaemic stroke, but NMDAR channel

blockers have failed to be translated into clinical stroke treatments. However, the opening of the NMDA receptor ion

channel requires occupation of two distinct binding sites, the glutamate site, and the glycine site. It has been shown that D-

serine, rather than glycine, can trigger the physiological NMDA receptor function. D-serine is a product of the activity of a

specific enzyme, serine racemase (SR). We will detect D-serine by measuring the hydrogen peroxide (H2O2) that results

from its oxidation by D-amino acid oxidase (Figure 1).

Figure 1: Enzymatic conversion of D-serine to hydrogen peroxide.

Professor Paul Dastoor’s lab at the Centre for Organic Electronics (COE), University of Newcastle is marrying the creation of

clever electronic inks with well-established printing technologies to address global challenges spanning health and

medicine. Professor Dastoor’s achievements and his research outcomes specially with the recent non-invasive, printable

saliva test strip for diabetic patients are well recognised. This project seeks to extend this exciting new technology to

develop organic thin film transistor (OTFT) sensors for D-serine by replacing glucose oxidase (GOD) with D-amino acid

oxidase.

The main chemical reaction catalysed by SR is the α, β elimination of water from L-serine to form D-serine, pyruvate, and

NH4. Reaction of D-Serine with D-amino acid oxidase forms H2O2, which in turn is then decomposed into hydrogen ions

which are detected by the OTFT device.

This project involves a multi-disciplinary collaboration focussed on the main aim of developing the first OTFT-based

sensors for D-serine. The project will help develop advanced skills in medical device fabrication technology and will

encompass building prototype sensors and testing their response to D-serine.

D) Laboratory Location; MSB309B and Physics Building facilities


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PROJECT DETAILS

A) Project Title: Blood brain barrier breakdown and early intracranial pressure rise following experimental stroke.


Primary Supervisor Name: Dr Daniel Beard

Location: Medical Science Building (MSB) 508


Phone: (02) 4921 7402

Co-Supervisor Name: Professor Neil Spratt



Phone: (02) 4921 6171

Co-Supervisor Name: Dr Kirsten Coupland



Phone: (02) 4921 7402


Background and Summary:

Ischemic stroke involves blockage of a blood vessel in the brain that disrupts cerebral blood flow. Following an ischaemic insult,

a penumbral region exists around a core of irreversibly damaged tissue. This penumbral region is supplied by collateral/’bypass’

blood vessels allowing the cells to survive for a limited amount of time. Timely reperfusion is a crucial goal for acute stroke

therapies. However, it may also contribute to a biphasic opening of the blood brain barrier (endothelial cell barrier between the

brain’s capillaries and the brain tissue) at 6 and 72 hours after reperfusion. This can cause excess water accumulation in the brain

(edema/brain swelling) and an increase in pressure within the skull (intracranial pressure, ICP).

Published data from our lab has identified that there is an increase in ICP at 24 hours after minor stroke, that is not assoc iated

with edema and can compromise blood flow to the brain, making brain damage worse. More recent unpublished work from our

lab has revealed that there is an earlier peak in ICP that occurs within the first 5 hours after reperfusion, around the same time

previous studies have shown early BBB opening. However, it is not known if the earlier ICP rise is associated with BBB opening in

our experimental model.

Rationale: Preventing this earlier ICP rise may be a new therapeutic target to improve blood flow to the brain in the first few

hours of reperfusion. By better understanding the cause of this ICP rise we may be able to design novel therapeutic strategies to

prevent it.

Aim: Determine whether early ICP elevation following experimental stroke is correlated with the degree of BBB opening and

edema formation.

Hypothesis: Early ICP elevation following experimental stroke will be positively correlated with the degree of BBB opening and

edema volume.

Experimental approach design:

Male, adult Wistar outbred rats underwent 2-hours of stroke (occlusion of the middle cerebral artery using the intraluminal

thread model) and 5 hours of reperfusion (n=10). ICP was monitored during stroke and reperfusion. The brains were collected at

the end of the experiment for histological analysis of infarct size and immunohistochemical analysis of BBB disruption will be

undertaken. Surgeries were performed by Dr Sara Azarpeykan. The prospective student will be in charge of working with the

brain tissue collected from these animals to optimise and run immunohistochemical stains for BBB opening (e.g.,

Immunoglobulin-G (Ig-G) and Albumin staining) as well as immunofluorescence analysis of markers of BBB integrity (e.g. claudin-

5 and Occludin). These stains will be analysed using image analysis software (Image J) and the degree of BBB opening will be

correlated with ICP recordings from the corresponding animals.

D) Laboratory Location: Medical Science Building (MSB) 504




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PROJECT DETAILS

A) Project Title: Neuroimmune interactions within the small airways of the lungs following

bushfire smoke exposure


Primary Supervisor Name: Dr. Henry Gomez

Location: Hunter Medical Research Institute (HMRI)


Phone: 40420832

Co-Supervisor Name : Dr. Melissa Tadros

Location: Medical Sciences Building, 3.12


Phone: 4921 5609



Background: Asthma affects 300 million individuals world-wide, and is characterised by recruitment of immune cells to the lungs and airways hyperresponsiveness. The 2019-2020 bushfire season resulted in a thick blanket of smoke descending on millions of Australians for weeks and months at a time without respite, causing asthmatic exacerbations and resulting in increased hospital admissions. We have developed a novel in vivo model of bushfire smoke exposure that recapitulates the features of particulate matter-induced asthmatic exacerbations such as airways hyperresponsiveness, and aberrant proinflammatory gene expression in the lungs. Importantly, there is a noted dynamic between neurobiological and immunological mechanisms in the lungs and this interplay, in the context of asthma, will be the focus of this project. Hypothesis: Bushfire smoke exposure induces neurobiological changes within the small airways of the lungs, with altered afferent and efferent communication contributing to airways hyperresponsiveness and mediation of immune cell interactions. Aim: To investigate the mechanisms by which bushfire smoke particulate exposure alters afferent and efferent nerve fibres in the small airways, and how these alterations contribute to the inflammatory profile observed in asthmatic lungs. Methods: The successful applicant will employ our novel bushfire smoke exposure models in their research. Highly specialised research techniques will be used such as precision cut lung slicing (PCLS) to investigate mechanisms of particulate matter-induced airways hyperresponsiveness. Sectioned and stained tissues will be used to determine histological features of disease such as collagen deposition and mucus secretion. Immunohistochemistry (IHC) and immunofluorescence (IF) will be employed to detect and localise factors of interest within histological sections, and highly specialised equipment and techniques will be used to measure lung function outcomes.

D) Laboratory Location: Hunter Medical Research Institute (HMRI).




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PROJECT DETAILS

A) Project Title: Development of a mouse model to examine the long term behavioural and

neurological impacts of infection with betacoronaviruses


Primary Supervisor Name: Rohan Walker

Location: HMRI


Phone:

Co-Supervisor Name: Nathan Bartlett

Location: HMRI


Phone: x20171

Co-Supervisor Name: Jason Girkin

Location: HMRI


Phone: x20847



Human pathogenetic betacoronaviruses such as endemic OC43 and pandemic SARS-CoV-2 are able

to infect the central nervous system (CNS). This is associated with both acute and prolonged

neurological symptoms such as long COVID which is a major concern as it holds back otherwise

healthy young individuals from returning to healthy active lives and return to work post-infection.

Despite the recognition that betacoronaviruses are neuroinvasive, the immunopathogenic

mechanisms linking this to neurological disease are poorly understood. This project will seek to

create a model of long-covid post OC43 infection (using a novel mouse respiratory OC43 infection

model). We will examine behavioural disturbances in mice either infected or not infected with

virus. Specifically, we will examine changes in weight, food consumption, locomotor behaviour

(using overhead cameras), and motivated behaviour using operant behaviour (time permitting).

We will also examine the duration of changes in neuro-inflammation post-infection, paying

particular attention to disturbances in microglia within the CNS and association with viral CNS

infection (highly sensitive detection of dsRNA by immunofluorescence microscopy). We

hypothesize that the persistence of behavioural disturbances will correlate with the severity of

neuro-inflammation linked to persistent low level infection. As a secondary goal, we will examine

the potential benefit of agents such as Modafinil (a non-addictive stimulant) to improve activity in

mice if they demonstrate evidence of long-covid like symptoms. For this later objective, we would

hypothesize that Modafinil will reduce the severity of behavioural disturbances induced by viral

infection.

D) Laboratory Location: HMRI


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PROJECT DETAILS

A) Project Title: How do pain signals alter spinal pain circuits


Primary Supervisor Name: Brett Graham

Location: UoN Callaghan Medical Sciences Building MS412


Phone: (02) 49215397

Co-Supervisor Name: Bob Callister

Location: UoN Callaghan Medical Sciences Building



Pain signalling is a complex function of the nervous system that requires processing at many levels.

One key site where pain signals are highly modifiable is within the spinal cord, where interplay

between raw signals arriving from the body and a variety of local spinal nerve cell types process this

information before refined pain codes are relayed to the brain via a critical population termed

projection neurons. Defining the important cell types and their connections in the spinal cord

remains a critical challenge to better understand, and then better treat pain, and our group has

actively contributed to progress in this area. This project focusses on our surprising discovery, that

projection neurons do not only send pain signals to the brain, but also send these signals back into

local spinal circuits via local branches known as collaterals. The significance of this local pain

feedback loop is entirely unknown. This project seeks to determine what types of nerve cells receive

the pain feedback signal, which will be critical in understanding the importance of these feedback

branches for our pain experience in health and disease. We hypothesise that these feedback

connections recruit local inhibitory nerve cells that control and limit pain signalling destined for the

brain. Loss of these important connects leads to exaggerated spinal pain signalling and pathological

pain experience. Mice will be prepared to express optogenetic (channelrhodopsin-2) or calcium

imaging (GCaMP6) proteins in projection neurons and then spinal cord sections will be used to map

the spinal nerve cell populations that receive synaptic input from projection neuron collateral

branches. The candidate for this project will gain experience in high-resolution patch clamp

electrophysiology, multi-labelling immunofluorescence confocal imaging, and real time network

analysis using calcium imaging to test our hypothesis and identify the nerve cells that receive local

feedback signals.

D) Laboratory Location – Callaghan Campus, Medical Sciences Building - MS412


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PROJECT DETAILS

A) Project Title: Optogenetic dissection of pain signalling from the spinal cord to the brain


Primary Supervisor Name: Brett Graham

Location: UoN Callaghan Medical Sciences Building MS412


Phone: (02) 49215397

Co-Supervisor Name: Bob Callister

Location: Medical Sciences Building



The sensation of pain arises as a complex mix of somatosensory and emotional experiences that are

critical for survival but also potentially devastating when they become pathological, as occurs in

chronic pain. Given this multifaceted and modifiable experience, it is not surprising that activity in a

variety of brain regions combine to produce pain. Pain signals are relayed to the brain via a

specialised group of spinal nerve cells termed projection neurons, and recently it has become clear

that these cells constitute a diverse population that codes different aspects of pain information.

Until recently it has been impossible to differentiate and decode these subsets of projection

neurons, however, the advent of optogenetics and intersectional viral techniques now makes this

possible. This project takes advantage of our groups extensive expertise using optogenetics

combined with behavioural assays and the development of several viral labelling techniques that

allow us to study specific projection neuron types. Experiments will study the behavioural outcome

of optogenetic activation of two non-overlapping projection neuron types: superficial projection

neurons; and deep lateral projection neurons. We hypothesise that the superficial population is

important for somatosensory aspects of pain, whereas the deep lateral population carries danger

signals that contribute to emotional pain experience and escape behaviours. Mice will be prepared

to express optogenetic proteins (channelrhodopsin-2) in each projection neuron type and then these

cells will be activated to characterise the associated behavioural outcomes. The candidate for this

project will gain experience in surgical techniques, viral technologies, new wireless optogenetic

equipment, detailed behavioural analyses, and neuroanatomical techniques for multi-labelling

immunofluorescence confocal imaging.

D) Laboratory Location – Callaghan Campus, Medical Sciences Building - MS412


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PROJECT DETAILS

A) Project Title: Impact of Bushfire smoke on respiratory immunity


Primary Supervisor Name: Dr Kurtis Budden



Phone: (02) 40420818

Co-Supervisor Name : Dr Gerard Kaiko

Location: Hunter Medical Research institute


Phone: (02) 40420184

Co-Supervisor Name: Dr Nikhil Awatade



Phone: 0424530299

Co-Supervisor Name : Prof. Peter Wark



Phone: (02) 40420110



The 2019 bushfires had a devastating effect and for months exposed people on the Eastern seaboard of

Australia to high levels of air pollution. We are part of a successful MRFF grant application to assess the impact

of bushfire smoke exposure on the lungs and immune system. We will elucidate the short and prolonged

physiological effects of bushfire smoke from different areas of Australia using our unique primary human cells

models of disease. We will assess the impact on cells from people with pre-existing chronic respiratory

diseases (asthma, COPD) and at different ages (pregnancy, infancy, elderly), and define safe exposure levels.

We will use a world first device to aerosolise the smoke and expose these cells to elucidate cell and tissue and

responses.

Our hypothesis is that bushfire smoke (BFS) promotes inflammation and damages airway epithelia, which is

exacerbated in patients with chronic respiratory diseases and differs by age.

To address this, the specific project aims will be:

1) Identify differences in the effects of BFS from different states on inflammatory responses and histopathological changes in primary bronchial epithelial cells from heathy human adults during acute (1-3 days) and chronic (14 days) exposures.

2) Characterise the effects of BFS on from human on inflammatory responses and histopathological changes in primary bronchial epithelial cells from COPD and asthma patients during acute (1-3 days) and chronic (14 days) exposures.


HMRI Building




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PROJECT DETAILS

A) Project Title: Assessing the impact of microbiome metabolites and diet on immune responses in COPD


Primary Supervisor Name: Professor Lisa Wood

Location: Medical Science Building/HMRI Building


Phone: 02 4921 7485

Co-Supervisor Name : Dr Kurtis Budden

Location: HMRI Building


Phone: 02 4042 0818

Co-Supervisor Name : Dr Hayley Scott

Location: HMRI Building


Phone: 02 4042 0113


approach:

Chronic Obstructive Pulmonary Disease (COPD) is a heterogenous condition caused primarily by cigarette smoking and

characterized by chronic inflammation, irreversible airway remodeling and alveolar destruction (emphysema). It is

currently the 3rd most common cause of death globally, and therapies are limited due to an incomplete understanding of

its pathogenesis.

Recent research in our lab has identified an important role of the gastrointestinal microbiome in COPD. This pulmonary-

gastrointestinal crosstalk, often termed the ‘gut-lung axis’, occurs due to a shared mucosal system between different body

sites exposed to the external environment. Antigens and metabolites, such as those produced by the gut microbiome,

regulate systemic immune function and influences susceptibility to infection or chronic inflammation at distal sites such as

the lung.

Diet is a major influence on the gut microbiome composition and metabolism, with subsequent impacts upon systemic

immunity and susceptibility to development of COPD. For example, high fibre diets increase microbial production of the

anti-inflammatory compounds short chain fatty acids. We hypothesise that dietary patterns and changes in microbiome

composition and metabolites are associated with systemic immune changes and measures of disease severity in COPD.

In this project, we aim to:

1) Assess the response of peripheral blood mononuclear cells (PBMCs) from COPD patients and age-matched healthy

controls to bacterial and viral antigens ex vivo.

2) Assess the impact of bacterial metabolites, including short chain fatty acids, on PBMCs from COPD patients and

age-matched healthy controls to bacterial and viral antigens ex vivo.

3) Characterise the relationship between dietary patterns, microbiome metabolites and PBMC responses to antigens

ex vivo.


HMRI Building


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PROJECT DETAILS

A) Project Title: Bushfire smoke particulate and its implication on the heart and lungs in regional Australia


Primary Supervisor Name: A/Prof Doan Ngo



Phone: 0240339386

Co-Supervisor Name : Dr Tatt Jhong Haw



Phone: N/A

Co-Supervisor Name : Dr Henry Gomez



Phone: x20832, 0410935446

Co-Supervisor Name : A/Prof Aaron Sverdlov



Phone: 0240420725


Particulate matters from urbanisation, industry pollution, and natural disasters (e.g., bushfire) can aggravate cardiopulmonary

health and lead to hospitalisation or death. There is no ‘safe’ lower exposure levels and adverse cardiopulmonary events can

occur at levels below current regulatory standards. As climate change abets more severe conditions, bushfire smoke particulate

exposure is becoming a major public health challenge and economic burden in Australia. In certain regions, this is further

complicated by high incidence of people with underlying cardiopulmonary disease and on-going exposure to other particulate

pollution from heavy industries. No study has yet to assess the impact of bushfire smoke exposure on cardiopulmonary health in

regional areas already afflicted by higher asthma burden and poor air quality. Thus, the impact of the catastrophic 2019/2020

Black Summer bushfires on cardiopulmonary health is unprecedented. Approximately 10 million Australians were exposed to

bushfire smoke for several months. Due to the severity and high populace exposure to 2019/2020 bushfire, it was imperative to

determine the impact of the prolonged bushfire smoke exposure on cardiopulmonary health of Australians, in particular those

living in regional/rural area with geographical co-localisation with heavy industries/mines.

We propose an exciting a pilot study using a combination of clinically relevant animal model of 2019/2020 bushfire smoke

exposure and human studies using primary human cardiac cells. We hypothesised that prolonged exposure to bushfire

particulate impairs cardiac function through direct damage cardiac cells and concomitantly induces exaggerated oxidative stress

to impair lung function. The main aims of the study are to 1) assess the cardiopulmonary impacts of bushfire smoke particulate

exposure, 2) delineate potential mechanisms, and 3) validate these findings in primary human cardiac cell cultures. Experimental

approach:

Aim 1: Bushfire smoke particulates (25µg/m3 or 100µg/m3) were administered intranasally to eight-week-old (adult) female

C57BL/6 mice daily for up to 2 weeks. A non-invasive live echocardiography will be performed to assess cardiac function of mice

at a day prior to bushfire particulate inoculation and a day prior to mice being culled on Day 3 and Day 14. Lung function analysis

will be performed on cull days.

Aim 2: Tissues (heart and lungs) will be collected for RNA and protein isolation. The expression levels of mRNA and protein targets

associated with lung function impairment and cardiotoxicity (e.g., inflammation, DNA damage, oxidative stress, and

mitochondrial dysfunction) will be assessed by qPCR and/or immunoblot assays. In addition, some of these tissues will be

perfused, inflated, formalin fixed, paraffin embedded, and sectioned (4–6 μm) for histological analysis (e.g., H&E and Masson’s

trichrome)

Aim 3: A dose response study will be performed to examine the cardiotoxicity of bushfire smoke particulates (25µg/m3 or

100µg/m3) on cardiac cells. Cardiotoxicity will be assessed in terms of cell viability at four timepoints (0, 24, 48 and 72 hrs) using

the Cell-Titre GloTM and/or LDH cytotoxicity assays. Cell lysates and culture supernatants will be collected and stored at -80°C

prior to assess mRNA (qPCR) and protein (ELISA/immunoblots) markers of inflammation and oxidative stress.

D) Laboratory Location:

Hunter Medical Research Institute, Level 3 East

Cardiometabolic/Cardio-oncology Research Group






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PROJECT DETAILS

A) Project Title: Prenatal physical activity, stress and mental health – downstream effects on offspring

development


Primary Supervisor Name: Dr Sarah Valkenborghs

Location: ATC205


Phone: 02 40420819

Co-Supervisor Name: Dr Marina Ilicic

Location: HMRI Level 3 East


Phone: 4042 0875

Co-Supervisor Name : Dr Tegan Grace



Phone: 4042 0345

Co-Supervisor Name : Prof Jonathan Hirst



Phone: 0413 961 638



Prenatal maternal stress is associated with poor neurodevelopment in offspring. Prenatal physical activity

may confer resilience to maternal psychosocial stress and nurture offspring neurodevelopment. This

project will investigate the cross-sectional relationship between prenatal physical activity with maternal

stress and mental health, and offspring neurodevelopment.

This pilot project will be conducted within the pre-existing and ongoing NEW1000 longitudinal cohort

study which aims to elucidate mechanisms responsible for the developmental origins of health and

disease (DOHaD). The NEW1000 study recruits pregnant women (currently n=10-15 per week) during

their first trimester through the John Hunter First Trimester Screening Clinic and follows them up at HMRI

throughout pregnancy, birth, and post-partum. Hair samples are collected at 20 weeks gestation, from

which cortisol can be isolated and used as a biomarker of psychosocial stress during the previous two

months. Participants wear an accelerometer for one-week to track their habitual physical activity levels

and also complete a battery of physical fitness tests and questionnaires on physical activity and mental

health. Infant development is assessed at 6-months post-partum.

Physical activity is associated with mental health in pregnant women but most are not physically active.

Elucidating fetal health benefits may motivate women to remain physically active during pregnancy.

D) Laboratory Location: This project will involve being located across both Callaghan (ATC building) and

HMRI (clinical trials unit and level 3 east wet lab) sites.






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PROJECT DETAILS

A) Project Title: Wnt pathway mediated regulation of epithelial-stromal cross talk in endometrial regeneration of

healthy and diseased uterus


Primary Supervisor Name: Prof. Pradeep Tanwar

Location: LS-229


Phone: 0249217280

Co-Supervisor Name: Dr Shafiq Syed

Location: LS-229


Phone: 0249217280

Co-Supervisor Name: Dr Muhammad Fairuz Jamaluddin

Location: LS-229


Phone: 0249217476


approach:

Uterus is arguably the most plastic organ in mammals that undergoes dramatic remodelling regeneration during

every menstrual cycle that too for >400 times in a woman’s reproductive lifetime. More importantly, while most

adult tissues in mammals undergo repair, a healing process that leaves the healed tissue weakened and scarred,

uterine endometrium is the only organ in the mammalian world that undergoes repeated regeneration without any

scar formation. Such an unprecedented regenerative ability can only be seen in mostly invertebrates, some

amphibians, and in fetal tissues during a brief window in the fetal developmental process. This has at least two

important implications. From the perspective of regenerative therapy, uterine endometrium presents itself as a

model system that provides a unique opportunity to investigate the mechanisms underlying the scarless

regeneration in the mammals itself rather than extrapolating the findings from the unrelated invertebrates or

amphibians. This will potentially give rise to novel therapies that can regenerate rather than repair any organ that

has undergone an acute or a chronic injury or a degenerative diseases leading to organ failure. From the perspective

of uterine biology, since most of the reproductive disorders, including infertility, endometrial cancer and

endometriosis are a result of aberrant endometrial regeneration, understanding the underlying mechanisms is

critical for the prevention and treatment of such disorders. Unfortunately, despite its critical importance, not much

is known about the basis of the endometrial scarless regeneration.

We have recently identified Axin2 as endometrial stem cells responsible for endometrial regeneration suggesting

that Wnt signalling plays a key role in this process. It is well known that this signalling pathway coordinates for both

stem cell proliferation and differentiation in most of the organs. However, our preliminary data shows that

endometrial epithelial Wnt signalling is dispensable for epithelial proliferation but not for stromal proliferation.

Interestingly, we have shown that aberrations in epithelial Wnt signals affect fibroblast activation/proliferation and

the macrophage functioning within the endometrial stroma resulting in regeneration failure.

Here, we hypothesise that endometrial epithelial proliferation is a complex regulatory process and that epithelial

Wnt signals regulate stromal cell proliferation and regeneration via epithelial-stromal cross talk. This project aims

to determine how endometrial epithelial and stromal proliferation are regulated following menses-induced

endometrial tissue sloughing. For that we will utilize human endometrial samples, human primary endometrial

organoids, single cell sequencing, proteomics, and our unique mouse models of menses and orthotopic human

endometrial transplantation models. In summary, this project will explore the complex signalling networks that

regulate the endometrial regeneration and provide valuable insights into how this process is unique in endometrium

such that it regrows scarlessly.

D) Laboratory Location: LS-229


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PROJECT DETAILS

A) Project Title: Diet, obesity, and the cell of origin for endometrial cancers


Primary Supervisor Name: Dr Shafiq Syed

Location: LS-229


Phone: 0249217280

Co-Supervisor Name: Prof. Pradeep Tanwar

Location: LS-229


Phone: 0249215148

Co-Supervisor Name: Dr Muhammad Fairuz Jamaluddin

Location: LS-229


Phone: 0249217476



Obesity is a global epidemic, has the strongest association with endometrial cancer (EC) among all

cancer types, and confers not only a 3-10-fold increase in its incidence, but also a 2-6-fold increase in

the risk of EC death. Unfortunately, the mechanisms underlying the obesity-driven endometrial

carcinogenesis are not known. In Australia, 3 in 5 women are obese, and as a result EC-deaths in NSW

alone have already increased by ~2x over last the 30yrs.

Most of the differentiated cells and non-stem cells (NSCs) in endometrium, even if mutated, are lost

every month during menses. Therefore, the most critical event in endometrial carcinogenesis is the

aberrations in endometrial stem cells (ESCs). With the rise of obesity in the Australian population,

understanding the relationship between diet, ESC biology, and EC incidence takes on great importance.

In our recent studies, we identified Axin2 as a marker of ESCs that also serve as the cell-of-origin for EC.

We have also shown that during EC initiation, b-catenin-mutated Axin2+ ESCs undergo clonal expansion

that bears a striking resemblance with the expansion of these stem cells in obese EC patients. We also

demonstrated the existence of a regulatory axis, consisting of the mTOR hyperactivation, between

visceral adipose tissue and endometrial glands.

Here we hypothesize that the nutrient sensing mTOR pathway mediates the in vivo effects of obesity in

ESCs during the EC initiation, and that obesity alters the metabolic program of ESCs or established

tumors, making them more reliant on fatty acids for their maintenance. This project aims to investigate

how obesity influences the functions of ESCs, their immediate progenies, and the cellular origins of EC.

For that we will utilize human endometrial samples, human primary endometrial organoids, single cell

sequencing, proteomics, and our novel orthotopic human endometrial transplantation model. In

summary, this project will explore

the mechanisms through which organismal diet, which has a profound impact on tissue regeneration,

aging, and disease in mammals, perturbs stem and progenitor cell biology and leads to diseases such as

cancer.

D) Laboratory Location: LS-229


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PROJECT DETAILS

A) Project Title: Exploring precision medicine for schizophrenia in vitro using patient derived

cells.


Primary Supervisor Name: Professor Murray Cairns

Location: MS512


Phone: 4921 8670

Co-Supervisor Name: William Reay

Location: MS616


Phone: 4921 5549



Schizophrenia is a psychotic disorder associated with a complex array of genetic and environmental

factors. From large genome wide association studies (GWAS), we now have an unprecedented

understanding of the genes and biological pathways that should lead to new drug targets with better

treatment outcomes. Unfortunately, this objective has been undermined by the tremendous

genomic heterogeneity among individuals, such that very few people share the same risk profile and

response to different treatments. Our laboratory is seeking to address this by tailoring both existing

and novel treatments to an individual’s biological architecture of polygenic risk. To test this

approach, we are studying a large cohort of research participants with schizophrenia that have

whole genome sequencing (WGS) and magnetic resonance imaging (MRI) of the brain. In a subset

we also have patient derived cells that can be cultured and treated with compounds to test the

genetically predicted drug response. The current study will test the hypothesis that cells from

individuals with higher polygenic risk for the disorder in biological pathways (receptive to specific

drugs) will display a greater response to these compounds than other participants and controls with

lower risk.

The aim of the project will be to culture cells derived from patients and non-psychiatric controls, and

measure the response to compounds implicated by the pathways enriched in GWAS of

schizophrenia. This project will involve genomic analysis of polygenic risk data (including

pharmagenic enrichment scores) from patients with schizophrenia and measure drug response

correlation in cultured cells using microscopy, biological assays and molecular analysis. This data will

be used to inform the use of this approach for precision medicine in schizophrenia.

D) Laboratory Location: MSB613


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PROJECT DETAILS

A) Project Title:

Functional analysis of the microbiome of colorectal surgery patients.


Primary Supervisor Name: Bridie Goggins

Location: HMRI


Phone: 40420283

Co-Supervisor Name: Emily Hoedt

Location: HMRI


Phone: 404 20384

Co-Supervisor Name: Peter Pockney

Location: HMRI


Phone: 0437697777


approach:

Anastomotic leaks (AL), when the rejoining of the bowel fails after diseased tissue has been removed, are the most severe

complication of the colorectal surgery required by patients with colorectal cancer and inflammatory bowel disease. The exact

cause is unclear and there has been little advance in preventing AL, which have a high mortality rate, over the last 50 years.

Our lab has recently completed 16S microbiome sequencing of mucosal swabs taken during colorectal surgery and identified

a microbial signature associated with AL cases (13% cases of 160 patients), suggesting that anastomotic leaks may be

associated with certain microbes. While 16S sequencing is a popular tool for the profiling of the microbial community it does

come with certain pitfalls. 16S sequencing primers carry a certain bias in the profiling of bacteria and altogether exclude the

mycobiome and virome. It also generates sequence data from amplicon data of a single gene (16S) and while there are tools

to predict functionality it does not match the accuracy of using shotgun metagenomics which uses no primers to generate

sequence of the whole genomic consortium.

We hypothesize that AL are caused by functional changes in the microbiome and this honours project aims to use shotgun

metagenomic sequencing on the samples from individuals who presented with an anastomotic leak and no leak “controls”

to identified strain and function level information on the “leak microbiome”. The student will use bioinformatic tools to verify

the microbial signatures previously identified with the 16S work in addition to investigating any signatures in the mycobiome,

virome, and functionality of the microbiome.

Additionally, we have mucosal swab samples stored in a microbial cryopreservative which facilitate culturing of the

microbiota. The student will use these samples to culture the microbiota of anastomotic leak patients. Using the results from

the 16S and shotgun metagenomic sequencing the student will use targeted culturing approaches to recovery microbes of

interest. These microbes/consortium will be used in vitro to assess their impact on healing.


HMRI Building – Level 3 East

John Hunter Hospital Campus

Lot 1 Kookaburra Circuit, New Lambton Heights

NSW, 2305


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PROJECT DETAILS

A) Project Title: Characterising mitochondrial function in bone marrow stem cells


Primary Supervisor Name: Doug Smith

Location: MSB


Phone:

Co-Supervisor Name: Gabrielle Briggs

Location: Surgical Services, John Hunter Hospital


Phone: 0249214495

Co-Supervisor Name: Zsolt Balogh

Location: Bone and Joint Institute, John Hunter Hospital


Phone: 0249214295



Due to our ageing population, osteoporotic fractures are on the rise and pose a significant burden to the

healthcare system and society, with a hip fracture occurring every 3 minutes in Australia and > $2

billion spent annually in Australia on fracture treatment. Time to union is longer with increasing age

and in the presence of osteoporosis. Delayed and non-union are associated with significant morbidity,

multiple unplanned hospitalisations, loss of mobility and independence, all of which increases mortality

in elderly. The underlying mechanisms for poor fracture healing in the elderly are poorly understood.

Following bone fracture, mesenchymal stem cells (MSCs) are the source of new bone, where they enter

the fracture site, proliferate and differentiate into cartilage producing cells (chondrocytes) and bone-

producing cells (osteoblasts). Both aged and osteoporotic fracture healing has been related to a reduced

number of MSCs, and a reduced and delayed ability to differentiate into chondrocytes and osteoblasts.

Aged MSCs and osteoblasts have been shown to have impaired mitochondrial function, however this

data has used animal models and to date there are no investigations of mitochondrial dysfunction in

elderly human MSCs. We hypothesise that MSCs isolated from elderly hip fracture patients will

have reduced mitochondrial function.

This project will be based at the John Hunter Hospital in the Surgical Sciences Lab. In this setting, we have access to bone marrow samples removed routinely during hip fracture surgery. The honours

student will test the above hypothesis by culturing MSCs from these samples in the laboratory,

measuring mitochondrial mass, membrane polarisation, OXPHOS and ATP production. In parallel, a

control group of bone marrow samples from young patients requiring surgical management of fractures

will be collected.


Surgical Sciences Laboratory, John Hunter Hospital



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PROJECT DETAILS

A) Project Title: Understanding the metabolism and mitochondria in the developing human

placenta

Supervisory Details :

Primary Supervisor Name: Professor Jon Hirst



Phone: 40420360. (Mob 0413 961 638)

Co-Supervisor Name: Dr Joshua Fisher



Phone:40420763

B) Background and Summary of Proposed Research, including a clear hypothesis, aims and


Summary Placental support of fetal growth and development in-utero are essential for lifelong health. Central to sufficient placental function is mitochondria, facilitating the metabolic changes, substrate utilisation and oxygen supply to the growing fetus. Detrimental changes in placental function involving mitochondria insufficiency is associated with many pregnancy complications including stillbirth and ongoing metabolic syndromes that lead to disability later in life. Despite this critical role, little is known about the metabolic changes across gestation, and how the mitochondria within the placenta facilitate and adapt to the altering environment to optimise healthy outcome. Aims This project will examine placental metabolism across gestation, and establish how the mitochondria differ between the first trimester and third trimester. Subsequently, this study will investigate the mechanisms which underpin the observed metabolic changes that lead to poor outcomes. Hypothesis We suspect that metabolic processes present in the first trimester are significantly different than those observed in the third trimester. Specifically, that first trimester metabolism will favour aerobic glycolysis over oxidative phosphorylation and alter their metabolic pathways accordingly. Experimental approach This project will be utilising new state of the art measures to assess metabolism and mitochondrial function, including real-time functional respiration (Agilent Seahorse), plate-based enzyme activity assays in addition to assessing gene expression and proteins. This will enable evaluation of the bioenergetic capacity and provide clear assessment of metabolic pathways. This project will provide the opportunity to develop a fundamental knowledge of metabolism and mitochondrial physiology, and develop skills in numerous laboratory techniques.

C) Laboratory Location

HMRI Level 3 East


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PROJECT DETAILS

A) Project Title: Targeting long noncoding RNAs to sensitize cancer to metabolic inhibition.


Primary Supervisor Name: Xu Dong Zhang

Location: LS3-49 Life sciences building, University Drive, Callaghan, NSW 2308, Australia


Phone: 49218906

Co-Supervisor Name : Yuchen Feng

Location: LS2-04 Life sciences building, University Drive, Callaghan, NSW 2308, Australia


Phone: 49261343



Long nonprotein-coding RNAs (lncRNAs) were historically thought to be transcriptional noise without biological function. However, it is now clear that they function to regulate diverse pathophysiological processes. Our previous studies have unveiled a number of lncRNAs which play important roles in cancer initiation, development and drug resistance. Targeting cancer cell metabolism has been emerging as a strategy for cancer treatment. Numerous studies have demonstrated that the mitochondrial oxidative phosphorylation (OXPHOS) system is necessary for cancer cell proliferation and survival. Therefore, OXPHOS has become a potential therapeutic target for cancer treatment. Indeed, small molecule OXPHOS inhibitors have already entered clinical evaluation. However, cancer cell resistance and adaptation to OXPHOS inhibition occurs. In this project, we’d like to explore lncRNA roles in the resistance of cancer cell to metabolic inhibition.

We have tested the responses of a panel of colorectal cancer (CRC) cell lines to an OXPHOS inhibitor, IACS-010759 (IACS), which inhibits mitochondrial complex I. Among them, we found that LIM1215 and Caco-2 cell lines were resistant to IACS treatment. Further RNA sequencing analysis identified a list of lncRNAs that were upregulated upon IACS treatment in IACS-resistant cell lines, suggesting the potential roles of these lncRNAs in protecting CRC cells from OXPHOS inhibition.

In this project, we aim to clarify lncRNA-mediated mechanisms responsible for the resistance of CRC cells to IACS treatment. The expression of candidate lncRNAs in cells before and after treatment with IACS will be tested using qPCR. Their functions will be examined using siRNA/shRNA and cDNA transfection/transduction, followed by cell viability, cell death and clonogenicity assays. LncRNA-binding proteins will be identified using RNA pulldown followed by mass spectrometry analysis. The interaction between lncRNA and proteins will be confirmed using RNA pulldown and RNA immunoprecipitation assays. These results will potentially identify lncRNAs that protect CRC cells from OXPHOS inhibition and develop RNA therapeutics by targeting lncRNAs as a strategy to sensitize CRC cells to OXPHOS inhibition.

D) Laboratory Location: LS3-20 Life sciences building, University Drive, Callaghan, NSW 2308.


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PROJECT DETAILS

A) Project Title: A genomic editing approach for indication the activation status of the autonomous

interferon signalling in colorectal cancer cells


Primary Supervisor Name: Xu Dong Zhang

Location: LS3-49, Life Sciences Building


Phone: (02) 4921 8906

Co-Supervisor Name : Ting La

Location: LS3-42, Life Sciences Building


Phone: (02) 4921 7970



Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the second most common cause of cancer death in Australia. Elimination of metastases, but not removal of the primary tumours, is the biggest obstacle to reduce the mortality caused by CRC. Chemotherapy is recommended in most metastatic cases as surgery is not possible to clear lesions at multiple sites. Of note, during the metastatic cascade, cancer cells tightly interact with the immune system. The outcome of chemotherapy can be influenced by the host immune system at multiple levels. Moreover, autonomous interferon signalling in cancer cells is potentially a trigger of the anti-cancer immune response and can also inhibit cell proliferation and induce cell death, and thus contribute to the efficacy of treatments. Of note, oxaliplatin is a first-line drug in the treatment of late stage of the disease, which were associated with activation of type I and type II interferon signalling.

An interferon-stimulated response element (ISRE) is a conserved nucleotide sequence responsible for the activity of Type I interferon-induced JAK/STAT signalling pathway. In this honours student project, we will develop an approach based on CRISPR/Cas9 technology to knock-in an enhanced green fluorescence protein (EGFP) gene under the control of multimerized ISRE into the safe harbor region in CRC cell lines (ISRE/EGFP cells) so that the activation status of the autonomous interferon signalling in the CRC cells could be visualised, tracked, and analysed by a flow cytometer or a fluorescence microscope based on the GFP levels.

A PhD project could be logically extended from this ISRE/GFP cell line, which we will further adapt a functional genetic screening platform to identify specific molecules that ignite the autonomous interferon signalling when the gene(s) is/are silenced in the cells based on this fluorescence system. The identified candidates will be further tested for development of novel approaches in the treatment of metastatic CRC.

In this project, we hypothesize that the ISRE/EGFP cells could indicate the activation status of autonomous interferon signalling and could be employed for the following functional screening. Our specific aims are: 1) To establish CRC cell lines containing multimerized ISRE controlled EGFP by CRISPR/Cas9; 2) To validate the activation of the autonomous interferon signalling in the knock-in cells by Oxaliplatin treatment.


The lab is located at Life Sciences Building (LSB3-20) at the main campus of Uni of Newcastle.


P a g e | 24

PROJECT DETAILS

A) Project Title: Investigation of pathological mechanisms of the schizophrenia risk gene mir137

during adolescence


Primary Supervisor Name: Lizzie Manning

Location: MS403


Phone: 49217857

Co-Supervisor Name : Murray Cairns

Location: MSB512


Phone: (02) 4921 8670



Schizophrenia is a severe mental illness affecting ~1-2% of the population that is

characterized by positive symptoms (e.g. psychosis and hallucinations), negative symptoms

(e.g. flattened emotions and social withdrawal), and cognitive deficits. While current

treatments are relatively effective for managing the positive symptoms of schizophrenia,

cognitive deficits are not improved by these and also make the greatest contribution to

functional impairment in patients.

Mir-137 is a microRNA that plays an important role in brain development and is also one of

the leading genetic risk factors for schizophrenia. Adolescence is considered to be an

important period for vulnerability for schizophrenia, however expression patterns of Mir-

137 and other microRNAs across adolescence are poorly understood. Adolescence is an

important period of protracted brain development in the prefrontal cortex, a region that is

important for cognitive functioning, and it is possible that disruption of adolescent Mir-137

expression during adolescence in schizophrenia causes abnormalities in prefrontal cortex

development that contribute to cognitive deficits in patients during adulthood. The goal of

this project is to 1) characterize the expression of microRNAs across adolescent

development in brain regions relevant to the pathophysiology of schizophrenia in that rat,

and 2) determine the effects of adolescent disruption of Mir-137 on cognitive functions in

adulthood. Successful applicants will receive training in molecular (gene expression) and

behavioural testing to complete these studies, and will be exposed to stereotaxic surgery

and calcium imaging methods that are likely to integrated in subsequent studies.

D) Laboratory Location: MS307 (CAL)


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PROJECT DETAILS

A) Project Title: Investigating pathways linking stress sensitive brain cells and action control

circuits


Primary Supervisor Name: Lizzie Manning

Location: MS403


Phone: 49217857

Co-Supervisor Name: Chris Dayas

Location: MS306

Email: 4921-5618

Phone: [email protected]



Repetitive actions in Tourette Syndrome (TS) are thought to arise through imbalance in basal

ganglia action-control circuitry. Interestingly, stress can trigger TS symptoms, and the

hypothalamic-pituitary-adrenal (HPA) stress hormone axis is hyperactive in TS; however, the

mechanisms linking stress to TS symptoms remain unknown. Corticotrophin-releasing-hormone

(CRH)-expressing neurons in the paraventricular-nucleus (PVN) of the hypothalamus sit at the

apex of the HPA axis, and were recently found to also control repetitive behavioral responses to

stress through synaptic (rather than hormonal) mechanisms.

This project is part of a 2-year grant aiming to characterize the function of a novel brain pathway

linking PVN-CRH neurons to the basal ganglia, using transgenic mice to selectively target CRH

neurons. The role of this pathway in stress-induced repetitive behaviors relevant to TS will be

examined across 3 aims in the project, of which this honours student will complete part of: 1)

recording neural activity associated with stress-induced repetitive behaviors in PVN-CRH

pathway to the Globus Pallidus externa (GPe) in the basal ganglia using fiber photometry; 2)

characterizing the impact of modulating PVN-CRH to GPe circuit activity on stress-induced

repetitive behaviors using optogenetics, and 3) identifying other targets of PVN-CRH cells in the

basal ganglia that may impact stress-induced repetitive behaviors using cell-type specific circuit

mapping.

This study will be the first to combine cutting-edge technologies to examine whether direct

synaptic connections between PVN-CRH and the basal ganglia mediate stress-induced

exacerbation of repetitive behavior, and how TS-relevant modulation of dopamine signaling

interacts with the functioning of this circuit. Together, these findings could open the door to

novel treatments that target PVN-CRH neurons, and their connections to basal ganglia, for the

treatment of TS.

D) Laboratory Location: MS307 (CAL)


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PROJECT DETAILS

A) Project Title: Overcoming therapy resistance in breast cancer by modulating the p53 pathway


Primary Supervisor Name: Kelly Kiejda

Location: Rm 3104, HMRI


Phone: 4042 0309

Co-Supervisor Name : Rodney Scott

Location: HMRI, Level 3 West


Phone: 0409926764



Breast cancer is the second-leading cause of cancer-related deaths in Australian women. DNA-

damaging therapies and anti-hormone therapies are commonly used in breast cancer treatment

and the majority of breast cancer deaths are caused by resistance to these treatments. To reduce

lives lost from breast cancer, it is necessary to understand the causes of treatment resistance. The

tumour suppressor p53 is essential for maintaining normal cell growth and repairing damaged

cells. Almost all therapies used in breast cancer activate this pathway. Isoforms of p53 have been

discovered, however, their functional relevance and relationship to treatment resistance is largely

unknown. We have shown that the p53 isoform- ∆40p53 is associated with aggressive breast

cancers (Carcinogenesis 2014;35(3):586–96) and worse outcome (Carcinogenesis 2016; 37:81-6).

Furthermore, high expression of ∆40p53 in breast cancer cell lines significantly reduced responses

to DNA-damaging therapies, but the effect on anti-hormone therapies is unknown. This project

will test the hypothesis that ∆40p53 promotes resistance to anti-hormone therapies.

Aim 1: To correlate the expression of ∆40p53, other p53 isoforms and hormone (estrogen)

signalling target genes with the response to hormones (estrogen) and anti-hormone therapies

(including tamoxifen) in a range of cell line models with different sensitivities to these agents.

Aim 2: To establish the pre-clinical efficacy of targeting ∆40p53 to increase sensitivity and alleviate

resistance to anti-hormone therapies.

The student will gain experience in 2D/3D cell culture assays, microscopy techniques, molecular

analysis, flow cytometry, western blotting, as well as a number of assays to investigate cell viability.

The student will join a highly supportive team and have access to cutting-edge laboratory

equipment and excellent mentoring. The new knowledge gained through this project will

contribute to a better understanding of p53 isoforms and will pave the way for the development

of pharmaceuticals to target p53 isoforms.


HMRI Level 3 West



P a g e | 27

PROJECT DETAILS

A) Project Title: Identification of novel therapeutic targets for the improved treatment of severe asthma


Primary Supervisor Name: Dr. Alexandra Brown



Phone: 0240420201

Co-Supervisor Name : C/Prof. Peter Wark



Phone: 0240420110

Co-Supervisor Name: Dr. Prabuddha Pathinayake



Phone: 0240420407



We have shown that ER stress is altered in severe asthma. However, whether ER stress plays a role in, is a consequence of, or can be therapeutically targeted for the treatment of disease, is yet to be fully explored. In this study, students will help conduct a complementary series of clinical (human data, cells and tissues) and experimental (mouse models) investigations to explore how ER stress is affected in the lungs in asthma and how the therapeutic targeting of ER stress, affects disease. This project is funded by the NHMRC Hypothesis: Endoplasmic reticulum (ER) stress plays an important role in the pathogenesis and severity of asthma. The therapeutic targeting of ER stress in asthma with FDA-approved drugs may represent an effective therapeutic for the treatment and/or prevention of disease. Aims: 1.) Define the molecular mechanisms of how ERS/UPR drives bronchial epithelial remodelling, with goblet cell

metaplasia and mucus hypersecretion, and airway fibrosis in severe asthma: We will grow primary bronchial

epithelial cells in air-liquid interface cultures and treat with, chemical ERS inducers, TH2 cytokines and

allergens and investigate molecular signalling pathways using qPCR, PCR arrays,westernblot, Elisa, RNA

sequencing etc.

2. Elucidate the role of ERS in crosstalk between airway epithelium and fibroblasts that drives airway remodelling

and fibrosis in severe asthma: We will establish an epithelial-fibroblast co-culture model and treat this model

with ERS inducers/inhibitors and examine airway remodelling and fibrosis markers using an array of

molecular techniques.

3. Elucidate the mechanistic role of ERS/UPR and therapeutic potential of chemical chaperones in airway

inflammation and remodelling in-vivo in experimental severe steroid-resistant asthma: We will use our

established murine models to see the effect of FDA approved ER stress inhibitors on controlling asthma

symptoms and investigate mechanisms how ER stress contributes to the pathogenesis of asthma.

D) Laboratory Location: Level 2 East and West, Hunter Medical Research Institute


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PROJECT DETAILS

A) Project Title: Investigating the role of hypothalamic populations in motivational deficits following

stress and sleep deprivation


Primary Supervisor Name: Chris Dayas

Location: MS306

Email: 4921-5618


Co-Supervisor Name : Lizzie Manning

Location: MS403


Phone: 49217857



Are stress-induced deficits hypothalamic of CRH cell activity associated with impairments in motivation

Stress is a leading risk factor for the development of depression. A debilitating feature of

depression is a loss of motivation. Corticotrophin releasing hormone (CRH) neurons in the

paraventricular nucleus (PVN) of the hypothalamus sit at the apex of the stress hormone

system (the HPA axis). These stress sensitive neurons orchestrate changes in behaviour and

physiology that depend on the release of the stress hormone cortisol (or corticosterone

(CORT) in rodents) from the adrenals. Importantly, recent work has established that CRH

neurons can also control stress related behaviour independent of CORT. Further, when we

used optogenetic stimulation to repeatedly activate CRH neurons, we found that this reduced

motivational behaviour, similar to how repeated/chronic stress can produce motivational

deficits and depression in humans. This project aims to understand how repeated stress

dysregulates the activity of CRH neurons to promote impairments in motivation.

To study CRH cell activity under stress CRH-cre mice will receive injections of the genetically encoded Ca2+ indicator gCaMP6f. Motivation after stress will be assessed using our well-established progressive ratio (PR) prcoedures. In a PR test, animals are first trained to perform an action (typically a lever press) to receive a reward e.g. something palatable like sucrose. After further training, PR testing demands that effort is increased exponentially to continue receiving a reward i.e. the lever pressing requirement to receive sucrose is increased exponentially. Eventually animals will cease to press, a point considered the “break point” which is considered an index of motivation or effort. We hypothesise that CRH cell activity is suppressed by repeated stress which will be associated with impairments in PR responding for sucrose. D) Laboratory Location: MS307 (CAL)


P a g e | 29

PROJECT DETAILS

A) Project Title: Investigating the role of hypothalamic populations in motivational deficits following

stress and sleep deprivation


Primary Supervisor Name: Chris Dayas

Location: MS306

Email: 4921-5618


Co-Supervisor Name : Assoc Prof Brett Graham

Location: MSB


Phone: + 49215397



Characterisation of a fast acting ventromedial hypothalamus to arcuate nucleus projection that

suppresses feeding.

Until recently, the only satiety promoting neurons known to exist in the brain were thought to be

arcuate nucleus (ARC) proopiomelanocortin (POMC) neurons. Genetic disruption of POMC and its

receptor leads to severe weight gain in mice and humans, although it typically takes 12-24 hours for

optogenetic stimulation of POMC neurons to reduce food intake. However, a novel population of fast-

acting glutamatergic neurons in the ARC that rapidly promotes satiety have been discovered. These

fast-acting ARC Vglut2 neurons are intermingled with POMC neurons in the ARC and rapidly

suppress food intake. This unexpected finding raises the question as to why the brain has evolved

fast and slow populations of satiety-promoting neurons. In the context of acute threat detection, a

rapid satiety response would seem advantageous to promote the shift towards avoidance behaviours.

Thus, we will test the hypothesis that VMH Vglut2 and fast-acting ARCVglut2 are synaptically

connected.

To address this question, we will establish the neural connectivity between VMH Vglut2 and

ARCVglut2 neurons using slice electrophysiology. In order to establish that VMH Vglut2 and

ARCVglut2 neurons are synaptically connected we will use slice electrophysiology in Vglut2 cre::R26-

LSL-tdTomato reporter mice bilaterally injected with AAV-EF1a-DIO-hChR2(H134R)-YFP into

theVMH (n=10). We will record ARCVglut2 td-tomato neurons during photostimulation of VMH

neurons (~50 neurons). In order to show that this circuit is modulated by hunger status, we will record

excitatory postsynaptic currents (EPSCs) on to ARCVglut2 tdtomato neurons in slices collected from

fed (n=10) and fasted mice (n=10). We will measure the intrinsic excitability (voltage-activated

currents), degree of spontaneous action potential (AP) discharge, and the characteristics of evoked

AP discharge using depolarizing step injections and predict greater excitatory inputs onto ARCVglut2

tdtomato neurons in fasted mice.

Outcomes: We predict that photostimulation of VMHVglut2 neurons will excite ARCVglut2 neurons in a monosynaptic manner and decreased excitatory input on to ARCVglut2 tdtomato neurons in the fasted state.

D) Laboratory Location: MS308/MS412 (CAL)


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PROJECT DETAILS

A) Project Title: Deciphering a novel molecular mechanism of therapy resistance in breast cancer.

B) Supervisory Details : as above

Primary Supervisor Name: A/Prof Nikki Verrills

Location: LS3-46


Phone: 4921 5619

Co-supervisor Name: Dr Severine Roselli

Location: LS3-47


Phone: 4921 5915

Co-Supervisor Name : Dr Heather Murray

Location: LS3-37


Phone: 4921 6934


approach:

Early detection and improved therapies have seen the survival rate for breast cancer significantly improve over the past

few decades. Despite this, breast cancer still kills over 3,000 Australian women every year. This is primarily due to disease

relapse and the development of resistance to therapy. Our laboratory has recently identified a novel mechanism by which

breast cancer cells become resistant to breast cancer therapies – reduced expression or genetic loss of a gene called

PPP2R2A. This gene encodes a regulatory subunit of the protein phosphatase 2A (PP2A), PP2A-B55α, that is a master

regulator of cellular growth, survival and differentiation pathways. Through analysis of human breast tumours and

molecular inhibition studies, we have discovered that reduced PP2A-B55α appears to confer resistance to endocrine

therapy (e.g. Tamoxifen) and targeted anti-HER2 and anti-EGFR therapies. However, to confirm this we must now test this

in a mouse model of breast cancer. To do this we have developed the world’s first PP2A-B55α knockout mouse and have

bred these mice with a genetically modified mouse model of breast cancer.

These unique mice are the ideal tool to test our hypothesis that reduced PP2A-B55α confers anti-breast cancer therapy

resistance by activation of specific PP2A substrates leading to constitutive activation of estrogen signalling growth and

survival pathways.

To test this hypothesis the project aims are to:

1. Test the anti-breast cancer efficacy of anti-HER2/EGFR therapy in wildtype and PP2A-B55α knockout mice

bearing HER2+ breast tumours

2. Perform proteomic and phosphoproteomic analyses of breast tumours from the wildtype and PP2A-B55α

knockout mice

3. Determine the functional importance of proteins/pathways identified in aim 2 using pharmacological and/or

molecular inhibition in human breast cancer cells

The student will be part of a passionate and dynamic research team and will learn a range of techniques including state of

the art mass-spectrometry based proteomics and phosphoproteomics, bioinformatics analyses, cell culture, cytotoxicity

assays, western blotting, animal handling and molecular techniques. The findings from this project will be published in a

high impact international journal and could identify novel therapeutic approaches for treating therapy-resistant breast

cancer.


Life Sciences Building LS3-26 and LS3-17





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PROJECT DETAILS

A) Project Title: Central role of a master regulator of cellular signalling in development, function and disease of the

epidermis

B) Supervisory Details : Dr Severine Roselli

Email:[email protected]

Phone: 49215915

Co-Supervisor Name : A/Prof Nikki Verrills

Location: LS3-46


Phone: 4921 5619

Co-Supervisor Name: Dr Heather Murray

Location: LS3-37

Email:[email protected]

Phone:


approach:

Protein phosphatase 2A (PP2A) is a master regulator of cellular signalling, controlling over 50% of

serine/threonine dephosphorylation in cells. We recently generated the first constitutive (full body) knockout

mouse model of the Ppp2r2a gene encoding the B55 regulatory subunit of PP2A which allowed us to reveal

some of its essential functions. Homozygous knockout of Ppp2r2a is embryonic lethal and associated with

strongly impaired skin formation, as well as limb and neural defects. The skin defect is characterized by

incomplete epidermal barrier acquisition, associated with poorly differentiated stratified epithelium with weak

attachment to the underlying basement membrane (Panicker et al 2020

https://www.frontiersin.org/articles/10.3389/fcell.2020.00358/full) .

These findings led us to hypothesize that B55 is involved in the regulation of keratinocyte cell adhesion to the

basement membrane, a crucial component of skin integrity and the wound healing process. To achieve this we

have generated a conditional knockout mouse where Ppp2r2a is deleted from keratinocytes. We are also

generating a conditional model where Ppp2r2a will be specifically deleted from fibroblasts. These two unique

models will enable us to define the relative contribution of B55 in the two major cell types of the skin.

This project will contribute to testing our hypothesis through the following aims:

Aim1- Characterize keratinocyte and fibroblast specific Ppp2r2a knockout mouse models.

Aim2- Characterize the keratinocyte adhesion defect to the underlying basement membrane using a combination

of skin tissue from the mice and human keratinocyte cell lines to allow wound healing in vitro studies.

Aim3- Perform proteomic and phosphoproteomic studies to decipher the network of signalling pathways

controlled by B55 in the skin.

Overall, the study will delineate the role of B55 in epidermal development, adhesion and wound healing, and thus could

lead to identification of new targets for a range of debilitating skin disorders. The student will be trained in cutting edge

biochemistry, cell biology and animal techniques in a dynamic laboratory environment, and the findings published in a high

impact international journal.


Life Sciences Building LS3-26 and LS3-17

https://www.frontiersin.org/articles/10.3389/fcell.2020.00358/full


P a g e | 32

PROJECT DETAILS

A) Project Title: Optimising therapies that cross the blood brain barrier for the treatment of diffuse

midline glioma


Primary Supervisor Name: A/PROF MATT DUN

Location: CALLAGHAN/LS327


Phone: 49215693

Co-Supervisor Name:

Location: Callaghan


Phone: 15148



Diffuse midline gliomas (DMGs) are highly aggressive brainstem tumours that grow within the structures of brain’s middle axis and are responsible for half of all brain cancer-related deaths in children worldwide. The brainstem controls life-essential functions such as heart rate, swallowing and breathing, meaning a tumour growing in this midline region has devastating consequences. Primarily diagnosed in children, patients and their families face a survival prognosis measured in months– a figure that has not improved despite decades of research.

Two key major hurdles preventing improved outcomes for DMG patients are i) the brain’s highly protective barrier (the ‘blood-brain barrier’ (BBB)) which prevents toxins in the peripheral bloodstream from passing into the brain, and ii) a lack of DMG specific therapies. The BBB precludes traditional chemotherapies from reaching (and selectively killing) DMG tumours, and hence development or enhancement of BBB-penetrable drugs is desperately needed.

PI3K/Akt/mTOR is an intracellular signalling pathway implicated in the growth, survival, and metabolism of almost all cancer types. In collaboration with researcher from the Hudson Institute of Medical Research, we performed CRISPR-Cas9 mediated genome wide deletion of 5,000 genes, revealing numerous genes mapping to the PI3K/Akt/mTOR axis are needed for DMG cell survival. This highlights the importance of simultaneous targeting multiple nodes of the oncopathways. Thanks to Material Transfer Agreements established with each respective company, A/Prof Dun has exclusive access to a suite of promising anti-DMG therapies known to penetrate the BBB: a) Paxalisib (Kazia Therapeutics) an orally-available, small molecule inhibitor of PI3K/Akt. b) “7” is a pan-mTOR inhibitor (Novartis International). iBET858 (GlaxoSmithKline) targets Bromodomain and extraterminal (BET) proteins activated downstream of PI3K/Akt/mTOR.

Therefore, the hypothesis of this study is that CNS optimised therapies targeting oncoproteins required for the survival of DMG will help to improve outcomes.

To provide preclinical confirmation of our hypothesis we will:

Aim 1: Utilise DMG patient-derived cell lines and assess downstream cell signalling following acute treatment with PI3K/mTOR and BRD inhibitors using phosphoproteomics.

Aim 2: Employ DMG PDX models to test the brain pharmacokinetics (PK) and pharmacodynamics (PD) of combinations of PI3K/mTOR and BRD inhibitors.

Aim 3: Assess the survival benefit of optimised combinations PI3K/mTOR and BRD inhibitors using a DMG patient derived xenograft mouse model.

D) Laboratory Location: LS327




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PROJECT DETAILS

A) Project Title: The role of the brainstem in asthma associated cough: does bushfire smoke exacerbate the

problem?


Primary Supervisor Name: Dr Melissa Tadros

Location: Medical Sciences Building 3.12


Phone: 4921 5609; 0405214782

Co-Supervisor Name: Dr Henry Gomez

Location: HMRI, Level 2 East


Phone: 40420832, 0410935446

Co-Supervisor Name: A/Prof. Anne Vertigan

Location: John Hunter Hospital


Phone: 49213726


approach:

Cough is initiated by airway irritation, whereby sensory receptors along the respiratory tree are activated and

transmit this information, via the vagus nerve, into brainstem centres associated with respiration. These signals

are then integrated into complex networks, resulting in activation of respiratory, airway and trunk musculature

to cause forceful expulsion of air, ie a cough. Alterations at any of the nodes in this pathway can change the way

an individual coughs, which can have a significant impact on quality of life. Individuals with asthma are at risk of

developing chronic cough, a condition which is exacerbated by exposure to irritants such as air pollution and

particulate matter.

Hypothesis: Asthmatic mice exposed to bushfire smoke will show greater neuronal and glial activation in their

brainstem cough centres and alterations in their sensory receptors within the upper airways compared to non-

asthmatic mice, and that this will be exacerbated in mice with severe asthma.

Aim 1: To investigate the activation of both neurons and glia within cough centres in the brainstem in control,

moderate and severe asthmatic exposed to low and high doses of bushfire smoke, and correlate these levels of

activation with physiological measurements of airway hyperresponsiveness.

Aim 2: To investigate the sensory nerve terminals and their receptors within the trachea of control, moderate

and severe asthmatic exposed to low and high doses of bushfire smoke, and correlate these changes with

physiological measurements of airway hyperresponsiveness.

Methods: The honours student will use a combination of anatomical techniques (embedding, sectioning, and

immunofluorescence) to assess both neurons and glia within the brainstem, as well as sensory nerve terminals

within the trachea. Automated cell counting and measurements of morphology will be applied to tissue

examining glial activation. Organ baths will be utilised to measure contractility of upper airway smooth muscles.

D) Laboratory Location: Medical Sciences Building, labs 3.12 and 4.14


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PROJECT DETAILS

A Project Title: Genetic and biological investigation of the relationship between susceptibility to infection with

schizophrenia: a role for C-reactive protein?

B Supervisory Details:

Primary Supervisor Name: Professor Murray Cairns

Location: MSB512, Medical Science Building, Callaghan


Phone: 49218670

Co-Supervisor Name: Dr Dylan Kiltschewskij

Location: MSB616, Medical Sciences Building, Callaghan


Phone: 49218748

Co-Supervisor Name: William Reay

Location: MS616


Phone: 4921 5549

C Background and Summary of Proposed Research, including a clear hypothesis, aims and experimental approach:

Background: Schizophrenia (SZ) is a psychotic disorder that arises from a complex interplay of genetic and environmental

factors. Epidemiological data suggests susceptibility to infections and alteration of inflammatory processes are involved in

SZ, however, the precise role of immunological factors in the disorder remains unclear. C-reactive protein (CRP), a peripheral

biomarker of inflammation, is particularly interesting because it contributes to the acute-phase inflammatory processes

during infection or tissue damage. While observational studies have identified elevation of serum CRP in individuals with SZ,

suggesting a potentially causal role mediated via aberrant inflammation, recent genetic analyses from our group suggests

elevated serum CRP exhibits a protective effect on SZ. Paradoxically, we also observed it to be associated with cortical

thinning in brain regions affected by the disorder. We therefore suspect these discordant findings may stem from complex,

recently discovered anti-inflammatory functions of CRP, however further investigation is required to further characterise

and explore the relationship between CRP, SZ, host responses to infection and general neuronal function.

Hypothesis and aims: We hypothesise that genetic risk for SZ is associated with CRP signalling, and these same genetic risk

factors also influence host-responses to infection. To address this, the following aims will be investigated:

1. To explore the relationship between SZ genetic risk, host antigen responses and CRP.

2. To experimentally characterise the implications of CRP dysregulation on neuronal morphology, integrity and gene

expression in vitro.

Research plan: The project will examine the relationship between SZ genetic risk and host IgG titres for 14 pathogens utilising

the UK Biobank cohort, consisting of over 500,000 individuals with matched genetic and serological data. The effect of

adjusting for measured and/or genetically proxied CRP on the association between antigen response and SZ genetic risk will

be quantified to establish whether it impacts this relationship.

The effect of CRP on neuronal properties will then be explored in cultured neurons via manipulation CRP concentrations. The

resultant impact on neuronal morphology, function, integrity and gene expression will be characterised by live cell

microscopy, multielectrode array, viability assays and total RNA sequencing, respectively.

D Laboratory Location MSB613


P a g e | 35

LIST OF APPROVED PROJECTS in alphabetical order by primary supervisor (have a student involved as of 8/11/21) Project Title: Examining endocannabinoid signalling in the gut-brain-axis in an animal model of

adolescent cannabinoid exposure

Supervisors: Dr Grace Burns, Prof Deborah Hodgson

Project Title: Understanding the gut-brain axis in pre-term babies and neonatal colitis

Supervisors: Dr Bridie Goggins, Dr Peter Pockney

Project Title: Investigating the effects of bushfire smoke exposure on maternal health, and

respiratory health of offspring

Supervisors: A/Prof Jay Horvat, Dr Alexandra Brown

Project Title: Developing a 3D-printed ‘gut-on-a-chip’ platform to study the gut-brain axis

Supervisors: Dr Gerard Kaiko, Prof Simon Keely

Project Title: Hypoxic signalling and the link between intestinal inflammation and colorectal cancer

Supervisors: Prof Simon Keely, Dr Emily Hoedt, Dr Grace Burns

Project Title: Investigation of a novel multipotent inflammasome inhibitor for the treatment of

influenza A virus infections

Supervisors: Dr Jemma Mayall, A/Prof Jay Horvat

Project Title: Role and therapeutic targeting of iron responses in influenza A virus infections

Supervisors: Dr Jemma Mayall, Dr Alexandra Brown

Project Title: Regulation of s(P)RR release from the placenta

Supervisors: A/Prof Kirsty Pringle, Prof Eugenie Lumbers, Dr Sarah Delforce, Dr Saije Morosin


P a g e | 36

Project Title: Unfurling the mechanisms of (P)RR driven placental development

Supervisors: A/Prof Kirsty Pringle, Prof Eugenie Lumbers, Dr Sarah Delforce, Dr Saije Morosin

Project Title: Characterising a new potential regulator of AML cell invasion

Supervisors: A/Prof Kathryn Skelding, A/Prof Lisa Lincz

Project Title: Examination of a Ca2+ modulator as a potential treatment for AML

Supervisors: A/Prof Kathryn Skelding, A/Prof Lisa Lincz

Project Title: Understanding the underpinnings of the declines in cholesterol and protein

homeostasis in the aging CNS

Supervisors: A/Prof Doug Smith, Dr Mitchell Cummins

Project Title: Fertility and sexual health knowledge and priorities in young people

Supervisors: Dr Jessie Sutherland, Dr Emmalee Ford

Project Title: The role of immune-cell derived exosomes in chlamydia infection and fertility

Supervisors: Dr Jessie Sutherland, Prof Eileen McLaughlin, Dr Elizabeth Bromfield

Project Title: Neuroimmune interactions associated with neuropsychiatric disorders following early

life inflammation

Supervisors: Dr Melissa Tadros, Dr Lauren Harms

Project Title: Development of Dried Blood Spot (DBS) Assays for Tyrosine Kinase Inhibitors

Supervisors: A/Prof Paul Tooney, A/Prof Jenny Schneider, Dr Peter Galettis

Project Title: Preclinical testing of novel combination therapies for acute myeloid leukaemia

Supervisors: A/Prof Nikki Verrills, Dr Heather Murray, Dr Joshua Brzozowski

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2022 SBSP BACHELOR OF BIOMEDICAL SCIENCES HONOURS PROJECT

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