Biomedical Science

Project

Do you have an interest in computational or statistical machine learning? No prior computational background necessary! You will learn important transferable research skills related to data handling, scientific writing, and advanced computational skills.

Every individual has an underlying genetic susceptibility for cancer development. Across all cancer types, the full complement of events driving tumour development still defies identification and, in many cases, no genetic drivers are found.

The successful applicant will use machine learning to predict the genomic elements active in driving common cancer types.

Detecting such alterations is fundamentally and technically challenging (combinatorially enormous number of ways that a genome can be altered), but our successfully established computational/bioinformatic approaches provide functional interpretation of the impact of genetic variation, genome structure, and gene expression to identify personalised risk factors.

Project

Healthy aging is accompanied by increases in inflammation, especially in the brain. Research into this neuroinflammation has been primarily focused on neurodegenerative diseases such as Alzheimer’s or Parkinson’s. However, neuroinflammation of the optic nerve can lead to glaucoma, a heterogenous group of diseases responsible for the most cases of permanent blindness worldwide, affecting up to 110 million people in the next decade. So if we use eye disease as a model of brain injury and brain age, can we then better understand and predict other neuroinflammatory diseases?

In spite of well-established treatments for glaucoma (i.e., lowering intraocular pressure), onset and progression often remains undetected and asymptomatic. This is because glaucoma, like many neurodegenerative diseases (Alzheimers, Parkinsons, etc), remains asymptomatic until severe neuronal damage (in this case, to the optic nerve) has already occurred. In fact, as diagnosis is made by thorough ophthalmological review, the exact symptoms that define early stages are controversial and diagnosis mostly happens only after a clinical visit initiated due to vision loss. Therefore, we want to know which clinical and genetic factors predispose individuals to a loss of visual acuity, including risk factors for glaucoma.

The successful applicant will learn how to develop novel machine learning models such as logistic regression, random forest, and adaptive boosting to utilise data on nearly 500,000 individuals as input into these predictive models, including thousands of environmental, physical, and biological parameters (including genetics).

Project

The discovery of new drug candidates for the investigation of validated drug targets is a cornerstone for advancing human health. This is typically achieved by the high throughput screening (HTS) of compound libraries against a disease-relevant target for the desired activity, however these methods are often either too slow, laborious, or costly, or present a very low hit rate.

DNA-encoded libraries (DELs) are a smart technology that have recently emerged to address this challenge. DELs are pooled binding assays that can be used to screen ultra-large collections of compounds (>108) for their affinity to an isolated protein or protein complex of interest (POI). DELs utilise recent advances such as next-generation sequencing to enable simultaneous and incredibly deep sampling of chemical space, at a fraction of the cost of standard HTS.

This project will leverage the existing ACSRC novel building block and intermediates collection to start building a DEL and establish this exciting new technology at the University of Auckland for the first time.

The successful applicant will gain exposure to the design, chemoinformatic analysis, synthesis and mass spectrometry analysis of DNA encoded compound libraries for drug screening.

Project

Neuroendocrine regions of our body can develop a cancer called Paraganglioma (PPGL). These cancers can spread throughout body to cause pain and death. Currently, the only way to cure localised PPGL is to cut it out, so if we could treat PPGL with a drug that could be taken by mouth, this would have advantages. A major form of PPGL that is highly prevalent in Māori is caused by a change (mutation) in the SDHB gene. When this mutated gene is expressed as a protein inside cancer cells, it gets destroyed, instead of performing its normal job, resulting in a progression of cancer.

Using a novel therapy called induced proximity, this project aims to identify small molecules that, when ultimately developed into drugs that can be given to the PPGL patients, will instruct the cancer to stop disposing of the SDHB protein, leading to cancer decline.

The successful applicant will synthesise novel small molecules to improve their binding affinity towards SDHB and serve as a template for an induced proximity approach to PPGL.

Project

PilVax is a novel peptide delivery platform that utilises the group A streptococcus (GAS) pilus structure (hair-like protrusions) to carry a stabilised and highly amplified peptide on the surface of the food-grade bacterium Lactococcus lactis. Proof-of-concept study showed that several loop regions in the structure of pilus backbone protein could be utilised as the peptide insertion site. Recombinant L. lactis strains expressing the modified pili on the surface were used to immunise mice intranasally, and elicited substantial systemic and mucosal antibody responses.

The aim of this project is to develop mucosal vaccines against respiratory syncytial virus (RSV) infection based on the PilVax technology.

RSV infection is the most common reason for hospitalisation of infants in developed countries, and causes high health burden in neonatal care in New Zealand and worldwide.

In this project, selected epitopes from the RSV R protein and F protein will be integrated into the pilus structure of GAS and expressed on the surface of Lactococcus lactis. Surface pilus expression and antigen presentation will be assessed by immunoblotting of the cell wall extract, as well as immunostaining of the whole bacteria using flow cytometry. Successful PilVax strains will be prepared as frozen stock for future immunisation studies.

Project

Perceptual dysfunction and vision loss occur in many disorders, ranging from eye diseases like glaucoma, neurological disorders like Alzheimer’s or Parkinson’s Disease, to stroke and head trauma. Commonly used procedures for mapping vision problems can lack reliability and are often tedious, resulting in patient fatigue and reduced task compliance.

In this project, we will trial novel behavioural procedures for measuring vision loss and perceptual anomalies. By presenting arrays comprising multiple stimuli and through the use of adaptive algorithms that home in on the patient’s performance we can reduce the time required for obtaining accurate measurements. We want to combine this with entertaining “gamified” tasks to make the test more engaging and thus boost compliance with task instructions. Our hope is to generate a battery of tests that are more suitable for use in patients, or other groups who might weary quickly of standard laboratory tasks (young children, elderly participants).

No prior skills are required, but some familiarity with computer programming (Matlab, Python) would not hurt.

The project will particular suit a creative mind for designing entertaining games and aesthetically pleasing stimuli.

Project

Managing severe and chronic pain in the hospital has become an increasingly challenging task. Opioids have been the traditional mainstay for treatment of severe pain, however decades of over prescription and abuse especially in the Western World has led to increasing number of opioid dependent patients who are resistant to opioid treatment. The financial burden of the opioid epidemic has been estimated to be $72 billion in the USA alone.

Opioid overuse can lead to hyperalgesia and analgesic tolerance, which result in ineffective pain control. Ketamine is a widely used non-opioid anaesthetic with profound analgesic properties and is known to reduce opioid hyperalgesia. Ketamine however produces psychotomimetic side-effects which limit its clinical potential.

The aim of this project is to synthesise novel analogues of ketamine, which retain its desired analgesic properties while eliminating its undesired side-effects. At the same time, we wish to test a novel delivery mode for the most successful analogue using a microneedle array system.

The project will expose the student to synthetic organic chemistry techniques and methods involved in development and evaluation of a novel drug delivery system.

Project

Stroke is a devastating disease with limited acute therapeutic options to improve outcomes. Successful hospital-level stroke treatment involves restoring blood flow to affected brain regions within the therapeutic window (typically 4.5-6 hours), which poses a significant logistical challenge for New Zealanders living in isolated rural regions.

In an animal stroke model, we recently found nebulised sodium nitrite reduced brain cell death and improved recovery, presumably due to its effects on improving brain blood flow. Nebulised sodium nitrite can be safely delivered by first responders, providing a potentially novel strategy to rapidly treat stroke patients inside the ambulance. However, the effects of nebulised sodium nitrite on brain blood flow in humans are currently unknown.

Using vascular and transcranial Doppler sonography to assess brain blood flow, this research will elucidate the effects of nebulised sodium nitrite on cerebrovascular control in healthy individuals.

Become a Manaaki Manawa student researcher!

Our Manaaki Manawa summer research scholars will have the opportunity to become a part of the Manaaki Manawa Centre for Heart Research. Manaaki Manawa will provide:

• A welcome event for our summer scholars so that you have a chance to meet each other, learn about the Centre’s work, have some kai and meet the Centre team, including our Pou Tikanga
• Hot desks if you need a place to work and our Outreach and Education Lead, who will be available to support you
• A celebration at the end of the scholarships with students doing presentations or posters about their research
• Continued connection with Manaaki Manawa after your project ends, with opportunities to continue with some research if you are interested, with support from our team and researchers, and to participate in Manaaki Manawa events throughout the year.
  

• A welcome event for our summer scholars so that you have a chance to meet each other, learn about the Centre’s work, have some kai and meet the Centre team, including our Pou Tikanga
• Hot desks if you need a place to work and our Outreach and Education Lead, who will be available to support you
• A celebration at the end of the scholarships with students doing presentations or posters about their research
• Continued connection with Manaaki Manawa after your project ends, with opportunities to continue with some research if you are interested, with support from our team and researchers, and to participate in Manaaki Manawa events throughout the year.
  

Project

In a mouse model of chronic obstructive pulmonary disease (COPD), a chronic inflammatory lung disease, pathogenesis is modulated by the gut microbiome. One member of the gut microbiome in particular, Parabacteroides goldsteinii, and its functional LPS component ameliorate lung inflammation. P. goldsteinii does not colonise the lung, so how does it exert its effect on the lung from the colon? Our hypothesis is that extracellular vesicles (EVs) derived from the outer membrane of the bacterium enable transport of the anti-inflammatory LPS to the lung. In this project we will isolate EVs from P. goldsteinii cultures and characterise them: size, numbers, protein and LPS content, anti-inflammatory activity. Techniques will include: Microbiology in a PC2 lab, anaerobic growth of Parabacteroides goldsteinii, isolation and purification of EVs, assays to quantify and size EVs purified, electron microscopy to demonstrate the presence of EVs, and the absence of other contaminating material, assays for protein, lipid and LPS, culture of mammalian cells and assays for anti-inflammatory activity.

Project

Diabetes is multifactorial, driven by different factors in different individuals, specifically the interactions between their genes and their environment. Our ability to design new drugs targeting different mechanisms is crucial for application of precision medicine in the future.

Research to date has not included all groups around the world and so we are focused on ensuring our Māori and Pacific peoples are included in the future of precision medicine for metabolic disease. To this aim we are studying several unique genetic variants that are associated with diabetes risk including the CREBRF variant.

We have several projects ideally suited to summer projects that are part of our ongoing large transgenic mouse studies; the students can come and learn qPCR, western blotting and histology and apply these methods to answer questions about how the variant is altering key biological processes to bring about diabetes protection in Māori and Pacific people. This is work we hope will lead to new therapeutic avenues in the future.

Project

Broth grown bacteria of isolates of methicillin sensitive Staphylococcus aureus (MSSA) have a minimum inhibitory concentration (MIC) of ˜2 µg/ml for flucloxacillin, an antibiotic that is active against beta lactamase producing S. aureus, but not methicillin resistant S. aureus (MRSA). Bacteria grown as a biofilm are not killed by 2 mg/ml flucloxacillin; 1000x more antibiotic than the MIC! When this biofilm biology occurs in an infection (and 70% of all infections are biofilms), it means an MSSA strain behaves like an MRSA and is much harder to treat. Lactoferrin, a multifunctional protein of the innate immune system, brings the biofilm eradication concentration for flucloxacillin back down to 20 µg/ml, although it does not kill biofilm alone. The antibiotic adjuvant activity of lactoferrin offers a new strategy to treat biofilm infections, and especially those MSSA infections that are still common in New Zealand, like osteomyelitis in children and prosthetic joint infections in older people.

How can we deliver the lactoferrin and flucloxacillin to the biofilm? Surgery is often needed to remove biofilm infection and associated dead, dying or infected tissue by debridement, but this is not always successful. We think this is a good time to add lactoferrin and flucloxacillin to deal with any residual biofilm. We propose sustained delivery from nanoparticles that we will load with lactoferrin, flucloxacillin or both lactoferrin and flucloxacillin.

In this project the successful applicant will investigate the biofilm killing potential of flucloxacillin with lactoferrin delivered as nanoparticles against MSSA.

Techniques may include: Nanoparticle production and characterisation, microbiology in a PC2 lab, growth of mature S. aureus biofilms in a bioreactor, biofilm eradication assays comparing the effectiveness of flucloxacillin, lactoferrin and flucloxacillin plus lactoferrin combinations, microscopy of biofilms to visualise biofilm killing or survival.

Depending on time and student interest/skills there may be an opportunity to expand areas of the project.

Project

Acute myeloid leukaemia (AML) is an extremely aggressive type of blood cancer that affects people of all ages. AML is mainly driven by a combination of various genetic mutations that arise in haematopoietic stem cells.

Our group has established several mouse models of AML, which have enabled us to study the molecular pathogenesis of the disease, perform an in-depth characterisation and test new treatment strategies. One such model is a knock-in model driven by the CALM-AF10 fusion gene, which is known to cause AML in human patients.

Using the CRISPR-Cas9 gene editing technology, we now aim to identify what other mutations co-operate with this fusion gene and lead to leukaemia development.

We have projects that are well suited for a summer student as part of our ongoing mouse studies. The successful applicant will have an opportunity to learn techniques in molecular biology (PCR, flow cytometry, genotyping of mouse samples, among others) and mammalian cell culture.

Project

Acute myeloid leukaemia (AML) is an aggressive, genetically heterogeeous blood cancer and the most common form of acute leukaemia in adults. Despite overall progress in AML studies, the standard treatments have not significantly changed over the past four decades, resulting in poor outcomes for patients. Therefore, it is crucial to explore new treatment strategies.

One approach we are taking is to repurpose existing FDA-approved drugs. Drug repurposing saves time and resources compared to developing new drugs from scratch.

In this project, we will be using a zebrafish model of leukaemia driven by a specific oncogene called MLL/AF9 to screen a collection of FDA-approved drugs and identify potential candidates that can reverse the disease's effects. Further, to better understand how these drugs work and their impact on normal and cancer cells, we will use RNA sequencing. This will allow us to analyse differentially expressed genes and the cellular pathways affected by the drugs.

The successful applicant will have the opportunity to learn various molecular biology techniques such as qPCR (quantitative polymerase chain reaction), microscopy of live zebrafish and zebrafish husbandry.

Project

Acute myeloid leukaemia (AML) is an aggressive type of blood cancer caused by genetic mutations. These mutations can stop cells from differentiating and increase cell proliferation.

We are using cutting-edge technology (such as a tissues-specific CRISPR-CAS9 system) to analyse the effects of mutations in DDX41, TET2, DNMT3A and ETV6 in zebrafish hematopoiesis. These genes are frequently found mutated in human AML.

In our study, we will use a variety of tools, such as quantitative PCR (qPCR), live imaging and flow cytometry, to study the effects of these mutations on zebrafish hematopoiesis.

This research has the potential to lead to new treatments for AML.

Project

Every day eight people in New Zealand hear the news that they have blood cancer. Acute myeloid leukaemia (AML), the most aggressive type of blood cancer, is a devastating disease with poor prognosis. Leukaemia stem cells (LSCs) initiate and drive AML. They can survive treatment, causing the disease to come back.

However, a specific treatment targeting LSC has so far not been possible. We recently discovered that by manipulating certain signalling pathway in AML cells we can eliminate LSC effectively in one of our mouse leukaemia models. We are in the process of replicating these findings with other leukaemia models, with the ultimate aim of translating these promising results to clinic.

The summer student will be embedded within a research group with experts on leukemia genetics, next generation sequence analysis and animal models of leukaemia.

Being exposed to this project will be an opportunity for the student to learn hands-on lab techniques (including primary cell culture, RNA work, qPCR) as well as gaining a broader appreciation of the basic haematology and leukaemia research field.

Project

Spiders (Trite planiceps) jump inaccurately in monochromatic light (jumping short of prey in red and over prey in blue light). Their principal camera-type eyes have a layered retina: cells in one layer contain green (535nm) sensitive visual pigment, while another is sensitive to red (626nm). It has been suggested that this layered structure allows computation of target distance by comparing image focus between layers.

This project will use micro-CT imaging of spider eyes to investigate whether rearing spiders under different wavelengths of light causes alterations in eye size, as found in other much larger, camera-type eyes of vertebrates and invertebrates. We will also investigate whether spiders improve jumping accuracy with time spent in monochromatic environments.

Project

The kidneys are crucial organs for waste excretion from the body and for maintaining the fluid and electrolyte balance of the blood. Damage to the kidney tubules caused by diabetes, hypertension, acute kidney injury by toxins, sepsis or ischemia, as well as congenital renal diseases, can progress to chronic kidney disease, which currently affects more than 10% of the population worldwide and is predicted to become the 5th leading cause of death by 2040.

In our lab, we use kidney organoids generated from induced pluripotent stem cells that represent in vitro grown human miniature kidneys and have been proven valuable tools for modelling various kidney disorders and developing new therapies (1-3).

To increase the clinical relevance of our model, we have recently established a new generation of kidney organoids by introducing an endothelial cell population providing the kidney’s vascular component.

The aim of this summer project is to determine the response of the kidney tubules and the vasculature to injury, manifesting in e.g. cell death, inflammation and oxidative stress.

These responses will be measured by qPCR analysis, immunohistochemistry and flow cytometry. The vascularised organoids will also be subjected to microfluidic culture, aiming to improve maturation of tubular and endothelial tissues.

If interested, please email your CV and academic transcript to arrange a chat about this project.

References

1. Przepiorski et al. “A Simple Bioreactor-Based Method to Generate Kidney Organoids from Pluripotent Stem Cells.” Stem Cell Reports, no. 2. doi:10.1016/j.stemcr.2018.06.018.
   
2. Digby et al. “Evaluation of Cisplatin-Induced Injury in Human Kidney Organoids.” American Journal of Physiology-Renal Physiology. doi:10.1152/ajprenal.00597.2019.
3. Dorison et al. “What Can We Learn from Kidney Organoids?” Kidney International. doi:10.1016/j.kint.2022.06.032.

Project

Polycystic kidney disease (PKD) is a common genetic disorder characterised by the formation of numerous cysts in the kidney, which can lead to gross enlargement of the organ, severe disruption of kidney function and ultimately kidney failure. PKD is predominantly caused by mutations in the PKD1 or PKD2 genes. Currently there is no cure for PKD, and treatment options are limited.

In our lab, we have introduced a PKD2 knockout mutation into human induced pluripotent stem cells using CRISPR/Cas9. Kidney organoids differentiated from these mutant cells recapitulate efficient cyst formation, thus represent a human in vitro model for PKD that is applicable to drug screening.

The aim of this Summer project is to screen a library of compounds on these cystic organoids for new drug candidates that can slow or reverse cyst growth.

Techniques will include measuring of cyst number and diameter, qPCR, immunohistochemistry and flow cytometry.

If interested, please email your CV and academic transcript to arrange a chat about this project.

Project

Insulin, consisting of 51 amino acids (5808 Da), is a large water-soluble protein used as a highly effective therapeutic for the management of patients with type 1 or type 2 diabetes mellitus who do not respond well to first line oral hypoglycaemic agents. As a protein drug used to treat diabetes, insulin has been conventionally administered via subcutaneous injection, many researchers have attempted to delivery insulin through other routes of administration, however the bioavailability is severely hampered by its inherent instability and it its low permeability to across biological membranes.

This project aims to develop and characterise polymeric nanoparticles for delivery of insulin and the formulation will also be investigated in vitro to determine cellular uptake and transport mechanisms using Caco-2 intestinal epithelial cells.

Project

The placenta is fetal organ that is critical for in-utero survival. The outer surface of the placenta is covered by the syncytiotrophoblast, a multinucleated single cell that is in direct contact with maternal blood.

As the exchange of oxygen and nutrients from mother to fetus, and the reciprocal exchange of waste products from the fetus to the mother occurs across the syncytiotrophoblast, adequate syncytiotrophoblast formation and function is crucial for healthy placental function and fetal growth/development.

Our lab uses 3D stem cell-derived models of the placenta to understand how the force of maternal blood flow across the placental surface (shear stress) impacts placental development and function.

This summer studentship aims to determine how well these stem cell models mimic placental mechanosensing, using immunohistochemistry and confocal microscopy to examine the expression of shear stress sensing proteins on the syncytiotrophoblast surface.

Knowing which mechanosensing proteins our model does/does not express is key for model validation, and will contribute to wider interdisciplinary Marsden-funded project aiming to understand how changing shear stress across the placenta in fetal growth restriction impacts placental function and fetal health: https://www.royalsociety.org.nz/what-we-do/funds-and-opportunities/marsden/awarded-grants/marsden-fund-highlights/2022-marsden-fund-highlights/how-does-blood-flow-affect-fetus-size/

If interested, please email your CV and academic transcript to arrange a chat about this project.

Project

Parkinson’s disease (PD) is the fastest-growing chronic neurological disorder affecting 10 million people worldwide. Current therapies are symptomatic and do nothing to stop disease progression. We know that alpha-synuclein aggregate formation is crucial in toxicity and progressive neurodegeneration. Still, it does not explain the variability in cell types affected and symptoms observed in patients with PD.

The recent identification of fibrillar alpha-synuclein aggregates with noticeable differences in structural and phenotypic traits led to the hypothesis that different alpha-synuclein 3D conformations or ‘strains’ may partly be responsible for the heterogeneous nature of PD. We hypothesise that the variability that occurs in PD can be stratified based on the alpha-synuclein strains and that effective treatment requires a strain-specific approach. Novel vital genes and proteins linked to the specific strains have been identified through RNA sequencing. Modifying these targets could lead to developing novel therapeutics to treat the underlying mechanisms of PD.

In this project, the successful applicant will validate the expression of newly identified targets in human brain sections from PD cases and normal tissue. You will identify cell-type specificity, protein localisation relative to alpha-synuclein aggregates, cellular compartments and regional variability throughout the brain.

Project

Parkinson’s disease is the fastest-growing chronic neurological disorder affecting 10 million people worldwide. Current therapies are symptomatic and do nothing to stop disease progression. We know that a-syn aggregate formation is crucial in toxicity and progressive neurodegeneration. Through RNA sequencing, we have recently identified novel vital genes and proteins involved in Parkinson’s disease.

We are ready for the next research phase now that we identified critical genes on the protein level. We will validate the expression in multiple brain regions and modification in vitro in human brain cells.

This research aims to modify the expression of these genes to slow the progression of Parkinson’s disease. If you want to participate in research that could lead to the development of novel therapeutics to stop Parkinson’s disease, then look no further.

In this project, the successful applicant will identify cell-type specificity, protein localisation relative to a-syn aggregates, cellular compartments, and regional variability throughout the brain. You will modify gene expression through RNAi and CRISPR.

Throughout this project, you will learn human brain anatomy and lab skills, including Western blotting, fluorescent immunohistochemistry, fluorescent imaging, cell culture, RNAi, CRISPR and automated image analysis.

Project

Persistent inflammation is the hallmark feature of chronic wounds, therefore anti-inflammatory therapy is often recommended. However, despite several years of research, clinical translation of these therapeutics has been impeded by the poor understanding of drug pharmacokinetics, stability and bioavailability. Thus, a safe and efficient drug delivery system is crucial to bridge the gap between our biomedical knowledge and preclinical studies to enable clinical translation and improve wound care.

This project aims to enable localised delivery of an anti-inflammatory drug for management of chronic wounds and support clinical translation.

The summer research project will involve formulation development, formulation characterization and evaluation of the drug bioavailability ex vivo.

Project

The efficacy of Tonabersat, a connexin hemichannel blocker, in management of inflammasome mediated ocular disorders is well established (1). However, delivery of therapeutically relevant drug concentrations to posterior ocular tissues remains an ongoing challenge.

This study aims to develop and validate a MALDI Imaging Mass Spectrometry method for evaluation of Tonabersat localisation in biological tissues.

The project will equip the successful applicant with analytical skills to perform MALDI-Imaging Mass Spectrometry analysis and enable the identification of appropriate drug delivery methods for preclinical and clinical translation of Tonabersat therapy.

Skills that the student will learn include tissue dissection, sectioning, mass spectrometry, data analysis, report writing.

Reference

(1) Mat Nor, M.N., I.D. Rupenthal, C.R. Green, and M.L. Acosta, Connexin Hemichannel Block Using Orally Delivered Tonabersat Improves Outcomes in Animal Models of Retinal Disease. Neurotherapeutics, 2020. 17(1): p. 371-387.

Project

Steroid-based eye drops, such as dexamethasone, are commonly used to treat ocular inflammatory conditions, and are very effective. However, the distribution of these drugs in the whole eye is not well understood and could cause deleterious effects. For example, posterior subcapsular cataracts are associated with ocular steroid use.

This project will develop a method for mapping steroid drugs in whole eyes using MALDI imaging mass spectrometry. This will inform our understanding of ocular steroid transport and delivery in the whole eye.

Skills learned during summer studentship

• Cryosectioning
• Imaging mass spectrometry
• Data analysis
• Report writing.
  

Project

Background: Various anaesthetic agents cause at a low dose cognitive impairment and eventually loss of consciousness. In anaesthesia this level of consciousness can be measured with EEG monitors. It is known that these monitors are not equally sensitive to the various anaesthetic monitors. This difference could be due to the different binding mechanisms of anaesthetic agents.

Previously, two novel quantitative EEG analysis algorithms have been developed that proved specifically sensitive to hyperbaric nitrogen and nitrous oxide. Their specificity has been explained as a difference in the receptor binding by these two agents.

Objective: This study aims to use the two analysis algorithms to test the hypothesis of receptor specific anaesthetic agents causing different EEG patterns by applying both algorithms to available EEG recordings of participants exposed to propofol, hyperbaric nitrogen, nitrous oxide and ketamine.

Methods: EEG recordings will be analysed in Matlab (computational software) with previous developed analysis algorithms.

Research impact: This research will help to increase the understanding of the binding mechanism different anaesthetic agents and the effect this has on the EEG recorded.

Skills learned during summer studentship

• Teamwork and research coordination skills
• Join the supervisors in recording EEG
• Quantitative EEG analysis with Matlab (previous programming experience is desirable)
• Oral presentation and scientific writing skills.

Output: Support the drafting of a journal article.

Project

The glymphatic system is a recently discovered pathway that plays a vital role in cleansing waste products from brain tissues. The fluid that bathes the brain (cerebrospinal fluid or CSF) has been shown to flow into the para-vascular space around the cerebral arteries. The movement of CSF is driven by the rhythmic contraction and relaxation of these penetrating arteries “pumping” CSF into the brain, collecting waste from the capillary beds then out via a corresponding pathway along the cerebral veins.

The glymphatic system is most active during sleep, and becomes impaired in diseases like hypertension and diabetes, as well as in sleep disorders, after cognitive injuries like stroke and concussion and in neurodegenerative diseases such as Alzheimer’s. It has been proposed that a reduced ability to “clean out” the brain may be responsible for the symptoms of cognitive impairment (“brain fog”) commonly associated with these conditions.

The arteries in the brain are heavily innervated by sympathetic nerves, which cause the arteries to constrict. We believe that the sympathetic nerves act as a “switch” able to turn the glymphatic system off (when sympathetic nerve activity is high) or on (when sympathetic nerve activity is low). We propose that an understanding of the autonomic control of glymphatic pathways is key to understand why these pathways become impaired in cardiovascular disease, where sympathetic activity is chronically elevated. These studies are part of a wider collaboration with Prof Jeffrey Iliff at the University of Washington: https://www.tedmed.com/talks/show?id=293015

This summer project will measure glymphatic clearance during activation and suppression of sympathetic activity to the cerebral blood vessels, and in preclinical models of hypertension and diabetes. It is anticipated that this will result in a high impact publication.

The successful applicant will join our friendly and supportive team in the Cardiovascular Autonomic Research Cluster.

This project would suit prospective students interested in the intersection of cardiovascular and neuro-physiology, and we are particularly keen to hear from students considering further postgraduate study.

Become a Manaaki Manawa student researcher!

Our Manaaki Manawa summer research scholars will have the opportunity to become a part of the Manaaki Manawa Centre for Heart Research. Manaaki Manawa will provide:

• A welcome event for our summer scholars so that you have a chance to meet each other, learn about the Centre’s work, have some kai and meet the Centre team, including our Pou Tikanga
• Hot desks if you need a place to work and our Outreach and Education Lead, who will be available to support you
• A celebration at the end of the scholarships with students doing presentations or posters about their research
• Continued connection with Manaaki Manawa after your project ends, with opportunities to continue with some research if you are interested, with support from our team and researchers, and to participate in Manaaki Manawa events throughout the year.
  

Project

The fundamental purpose of blood pressure is to facilitate the delivery of adequate blood flow to every organ in our body. However, the relationship between blood pressure and blood flow is not linear. Instead, a range of intrinsic and extrinsic mechanisms continuously constrict and dilate the blood vessels, to ensure that blood flow is matched to the metabolic demands of the tissue or organ being supplied.

Recent data reveals that the relationship between the “supply” pressure and the blood flow to organs can be chronically altered under disease states such as hypertension, or acutely altered by changes in autonomic nervous system activity. We have used cutting edge technologies to investigate the pressure-flow relationship under conditions of health and cardiovascular disease (hypertension), and during interventions to challenge the pressure-flow relationship. We have directly measured high-resolution (beat to beat) blood pressure and blood flow to highly metabolically active “consumer” organs such as the brain, which at rest requires ~20% of total cardiac output despite only consisting 2% of body weight.

We would like to examine “steady state” differences between (for example) data from subjects with high blood pressure, compared to those with normal blood pressure. Bidirectional feedback models would permit us to examine the potential directionality of pressure-flow modulation; it is well-established that pressure is a key driver of flow (pressure to flow), but we also believe that the reverse may also be true (i.e. flow to pressure). A detailed understanding of the pressure-flow relationship is essential to help us understand how organ perfusion is maintained in health and may be impaired under conditions of cardiovascular disease.

Outcome: To use methodological and modelling approaches to interrogate the relationship between blood pressure and brain blood flow under different physiological and pathological conditions.

Become a Manaaki Manawa student researcher!

Our Manaaki Manawa summer research scholars will have the opportunity to become a part of the Manaaki Manawa Centre for Heart Research. Manaaki Manawa will provide:

• A welcome event for our summer scholars so that you have a chance to meet each other, learn about the Centre’s work, have some kai and meet the Centre team, including our Pou Tikanga
• Hot desks if you need a place to work and our Outreach and Education Lead, who will be available to support you
• A celebration at the end of the scholarships with students doing presentations or posters about their research
• Continued connection with Manaaki Manawa after your project ends, with opportunities to continue with some research if you are interested, with support from our team and researchers, and to participate in Manaaki Manawa events throughout the year.
  

Project

Stroke is one of the leading causes of mortality and long-term disability in New Zealand which disproportionally affect Māori and Pacific populations.

While effective hospital-level interventions improve stroke patient outcomes, only a fifth of all stroke patients are eligible due to narrow treatment windows. Nebulized sodium nitrite is a potential strategy for extending the stroke treatment windows by selectively increasing blood flow to ischaemic brain regions.

Using an animal-stroke model, this project will examine the therapeutic potential of nebulized sodium nitrite in improving brain blood flow and functional outcomes following ischaemic stroke.

Nebulized sodium nitrite has the potential to be administered quickly after stroke onset by first-responders, which could improve access for patients in geographically remote areas within New Zealand.

Improving hyper-acute stroke management with supportive therapies could significantly improve healthcare for all Māori, but especially for the rural Māori communities. For these reasons, nebulized sodium nitrite has a huge potential to be translated into clinical practice rapidly and help reduce health inequity in New Zealand.

The successful applicant will join our friendly and supportive team in the Cardiovascular Autonomic Research Cluster.

The studentship will require the applicant to perform integrative physiological research.

The ideal candidate will need to have a keen interest in translational research and be comfortable working in a laboratory environment. We are particularly keen to hear from students considering further postgraduate study.

Become a Manaaki Manawa student researcher!

Our Manaaki Manawa summer research scholars will have the opportunity to become a part of the Manaaki Manawa Centre for Heart Research. Manaaki Manawa will provide:

• A welcome event for our summer scholars so that you have a chance to meet each other, learn about the Centre’s work, have some kai and meet the Centre team, including our Pou Tikanga
• Hot desks if you need a place to work and our Outreach and Education Lead, who will be available to support you
• A celebration at the end of the scholarships with students doing presentations or posters about their research
• Continued connection with Manaaki Manawa after your project ends, with opportunities to continue with some research if you are interested, with support from our team and researchers, and to participate in Manaaki Manawa events throughout the year.
  

Project

Background: Diabetes is Aotearoa’s fastest-growing disease, with approximately 6% of the total population affected, becoming the global epicenter. In diabetes, sympathetic nerve activity (SNA) controlling blood sugar is dramatically increased and contributes to poor blood sugar control. Recent studies discovered that carotid bodies (CB) sense blood sugar and/or insulin and cause increases in SNA, whereas their removal lowers blood sugar, blood pressure, and SNA. We have discovered two novel receptors within the CB that control blood sugar via modulating SNA. These data will advance our understanding of the mechanisms of cardiometabolic diseases and will inform unique treatment strategies for treating diabetes and hypertension.

Research Skills: Our team is part of the Cardiovascular Autonomic Research Cluster (CVARC) in the Department of Physiology. We have multiple lines of research evaluating cardiometabolic profiles and the impact of therapeutic agents in pre-clinical settings.

The successful applicant will work with a diabetic and hypertensive model in rats, analyzing and quantifying blood components, covering multiple techniques, specifically with ELIZA.

Become a Manaaki Manawa student researcher!

Our Manaaki Manawa summer research scholars will have the opportunity to become a part of the Manaaki Manawa Centre for Heart Research. Manaaki Manawa will provide:

• A welcome event for our summer scholars so that you have a chance to meet each other, learn about the Centre’s work, have some kai and meet the Centre team, including our Pou Tikanga
• Hot desks if you need a place to work and our Outreach and Education Lead, who will be available to support you
• A celebration at the end of the scholarships with students doing presentations or posters about their research
• Continued connection with Manaaki Manawa after your project ends, with opportunities to continue with some research if you are interested, with support from our team and researchers, and to participate in Manaaki Manawa events throughout the year.
  

Project

Cardiovascular disease (CVD) is the single biggest killer of women in New Zealand.

Evidence strongly indicates that gestational diabetes (GDM, diabetes during pregnancy) is an independent risk factor for future heart disease risk. Yet, fundamental links between GDM and later adverse health outcomes remain unclear.

Hyperactivity of the sympathetic nervous system (fight or flight response) is associated with cardiovascular and metabolic diseases in obesity, metabolic syndrome, and type 2 diabetes. In non-pregnant humans, insulin resistance, hyperglycaemia, and hyperinsulinemia can either lead to, and/or be caused by, sympathetic hyperactivity. The peripheral chemo reflex (the carotid bodies (CBs)) is an important regulator of blood glucose via modulation of sympathetic activity. Over-activation of CBs has a critical role in inducing insulin resistance through excessive sympathetic activation and reducing CB activity via CB denervation (CBD) has been shown to be beneficial for cardio-metabolic health.

Understanding how CB activity changes during pregnancy and how it could contribute to GDM in the mother would pave the path to both early detection of disease and novel prophylactic interventions.

In this regard, the aim of this summer studentship is to characterise the molecular differences in carotid bodies and placental tissues between our pre-clinical rodent models of pregnancy and GDM.

Skills taught during summer studentship

• Tissue processing
• Immunohistochemistry
• PCR
• Data analysis.

Become a Manaaki Manawa student researcher!

Our Manaaki Manawa summer research scholars will have the opportunity to become a part of the Manaaki Manawa Centre for Heart Research. Manaaki Manawa will provide:

• A welcome event for our summer scholars so that you have a chance to meet each other, learn about the Centre’s work, have some kai and meet the Centre team, including our Pou Tikanga
• Hot desks if you need a place to work and our Outreach and Education Lead, who will be available to support you
• A celebration at the end of the scholarships with students doing presentations or posters about their research
• Continued connection with Manaaki Manawa after your project ends, with opportunities to continue with some research if you are interested, with support from our team and researchers, and to participate in Manaaki Manawa events throughout the year.
  

Project

Antimicrobial resistance poses an increasing threat to global health. With the growing prevalence of multi-drug resistant (MDR) organisms, it is imperative to find alternative approaches. Currently the last-line therapy for defence against these Gram-negative multi-drug resistant organisms (MDROs) is a class of antibiotic called polymyxins. Polymyxins work by targeting the negatively charged lipid A domain of the lipopolysaccharides (LPS) present in the outer cell membrane of Gram-negative bacteria. The most significant adverse effect of polymyxins is their nephrotoxicity, which has historically limited their clinical use.

Novel polymyxin B (PMB) analogues that maintain the efficacy of the original compound, but with reduced toxicity have been developed by our collaborators at School of Chemical Sciences/School of Biological Sciences/Maurice Wilkins Centre.

In this project the successful applicant will investigate the antibiofilm activity of novel PMB against Gram-negative bacteria.

Techniques will include microbiology in a PC2 lab, growth of clinically relevant bacterial strains as biofilms in a bioreactor, eradication assays and visualising of biofilms using microscopy.

This summer studentship can be continued towards Honours, Masters or PhD studies.

If interested, please email your CV and academic transcript to arrange a chat about this project.

Project

The targetted outgrowth of neuronal axons and dendrites (neurites) is a key stage of early brain development, and is fundamental for establishing the healthy brain functions needed throughout the rest of our lives. Many developmental neurological disorders show a pattern of dysregulated neural circuitry, although the underlying molecular mechanisms remain to be resolved.

Our laboratory explores the role of the extracellular matrix in brain development, using in vitro and in vivo models. Hyaluronan is a unique sugar, synthesised directly on the neuronal membranes, and present particularly on growing neurite tips.

This summer studentship will utilise molecular biology and microscopy methods to characterise changes in neuronal hyaluronan in models of hypoxic and inflammation-induced developmental neural injury.

Skills

• Neuronal cell culture
• Light microscopy
• Molecular biology: Hyaluronan Quantification Enzyme linked immunosorbent assays (ELISA) and immunocytochemistry
• Data analysis.
  

Project

Many lower-grade gliomas (WHO brain tumour grades, II – III) often transition into high-grade gliomas, such as glioblastoma. Predicting which patient tumours are likely to rapidly transition into high-grade tumours will enable clinicians to make informed decisions on the management of these tumours at an early stage. However, there is a lack of definitive protein-based biomarkers that allow for these predictions.

We propose that PSA-NCAM, a neuromigratory molecule found in neural stem cells, could act as a predictor of high-grade transition. Our team has shown that PSA-NCAM accurately delineates different grades of gliomas and strongly predicts patient outcomes even within high-grade gliomas. We, therefore, hypothesise that higher PSA-NCAM levels detected in lower-grade glioma specimens will correlate with faster disease progression in these patients, thus, acting as a novel biomarker for rapid low-grade to high-grade tumour transition.

The aim of this studentship is to pilot this hypothesis using 20 lower-grade glioma specimens and correlate their PSA-NCAM expression levels with disease progression.

The successful applicant will learn how to work with human brain tumour specimens, undergo multiplex immunohistochemistry techniques, operate automated microscopy, and use machine learning to correlate protein expression with clinical outcomes.

Project

Background: At FMHS we have a system (Pathobin) that creates photorealistic 3D digital images of human organs to enable students to have an interactive learning experience. The 3D images are hosted in image libraries that can be accessed online from anywhere at any time.

Objective: The student will capture a sequence of high-resolution images of our collection of human anatomy models and organs using an automatically rotating turntable, and high-resolution DSLR camera. In addition to capturing 3D images, the student will investigate the feasibility of different UoA online image hosting platforms. This will support online and blended learning and build the skill set of relevant FMHS staff.

Methods and skill required: The technique is 3D photogrammetry and video demonstration can be watched: https://www.youtube.com/watch?v=YpIGAIQZ0ek

Ideal candidates will be interested in photography and imaging editing software, be proactive in problem-solving, and comfortable handling human organs and tissues. This project involves two students working together as a team.

Research impact: Through this project, we hope to continue driving innovative learning methodologies within our School of Medical Sciences, ensuring our teaching remains engaging, accessible, and effective for all students.

Skills learnt: 3D photogrammetry, data processing, hosting, and human anatomy.

Output: The images are viewed in a pdf. In this project, you will help build the FMHS online 3D image library for teaching as well as learning human anatomy. You will compare specimen preservation of fresh-frozen, fixed and plastinated specimens for optimal photorealistic image output.

References

Turchini, John, Michael E. Buckland, Anthony J. Gill, and Shane Battye. ‘Three-Dimensional Pathology Specimen Modeling Using “Structure-From-Motion” Photogrammetry: A Powerful New Tool for Surgical Pathology’. Archives of Pathology & Laboratory Medicine 142, no. 11 (November 2018): 1415–20. https://doi.org/10.5858/arpa.2017-0145-OA.

Bois, Melanie C., Jonathan M. Morris, Jennifer M. Boland, Nicole L. Larson, Emily F. Scharrer, Marie-Christine Aubry, and Joseph J. Maleszewski. ‘Three-Dimensional Surface Imaging and Printing in Anatomic Pathology’. Journal of Pathology Informatics 12, no. 1 (1 January 2021): 22. https://doi.org/10.4103/jpi.jpi_8_21.

Project

Background: At FMHS we have a system (Pathobin) that creates photorealistic 3D digital images of human organs to enable students to have an interactive learning experience. The 3D images are hosted in image libraries that can be accessed online from anywhere at any time.

Objective: The student will process high-resolution images of our collection of human anatomy models and organs into 3D pdf format using the Pathobin 3D online system. The student will incorporate these images into a user-friendly 3D image library and annotate them to enhance understanding. This will support online and blended learning and build the skill set of relevant FMHS staff.

Methods and skill required: The technique is 3D photogrammetry and a video demonstration can be watched: https://www.youtube.com/watch?v=YpIGAIQZ0ek

Ideal candidates will be interested in photography and imaging editing software, be proactive in problem-solving, and comfortable handling human organs and tissues. This project involves two students working together as a team.

Research impact: Through this project, we hope to continue driving innovative learning methodologies within our School of Medical Sciences, ensuring our teaching remains engaging, accessible, and effective for all students.

Skills learnt: 3D photogrammetry, data processing, hosting, and human anatomy.

Output: The images are viewed in a pdf. In this project, you will help build the FMHS online 3D image library for teaching as well as learning human anatomy. You will compare specimen preservation of fresh-frozen, fixed and plastinated specimens for optimal photorealistic image output.

References

Turchini, John, Michael E. Buckland, Anthony J. Gill, and Shane Battye. ‘Three-Dimensional Pathology Specimen Modeling Using “Structure-From-Motion” Photogrammetry: A Powerful New Tool for Surgical Pathology’. Archives of Pathology & Laboratory Medicine 142, no. 11 (November 2018): 1415–20. https://doi.org/10.5858/arpa.2017-0145-OA.

Bois, Melanie C., Jonathan M. Morris, Jennifer M. Boland, Nicole L. Larson, Emily F. Scharrer, Marie-Christine Aubry, and Joseph J. Maleszewski. ‘Three-Dimensional Surface Imaging and Printing in Anatomic Pathology’. Journal of Pathology Informatics 12, no. 1 (1 January 2021): 22. https://doi.org/10.4103/jpi.jpi_8_21.

Project

The lymphatic vasculature is essential for fluid homeostasis in the body. When lymphatic vessels are obstructed or damaged this results in lymphoedema, the painful and debilitating accumulation of lymph in tissues. Secondary lymphoedema is one of the most significant survivorship issues following surgical and/or radiological treatment for tumours and is caused by incomplete lymphatic growth following lymph node removal.

Almost nothing is known about how lymphatic growth is regulated. To help further our knowledge of this process, we have isolated mutant zebrafish which display either undergrowth or overgrowth of lymphatic vessels.

This project will help characterise these lymphatic mutants to uncover the genetics that control lymphatic vessel growth.

Experiments could involve

1. Imaging lymphatic vessel growth in mutant fish
2. Mapping genetic mutants to find causative mutations
3. Experiments focused on the validation of candidate mutations i.e. CRISPR/Cas9, gene knockdowns, gene over-expression.

Skills

• Model organism genetics
• Live cell imaging
• Zebrafish husbandry

References

Britto DD, He J, Misa JP, Chen W, Kakadia PM, Grimm L, Herbert CD, Crosier KE, Crosier PS, Bohlander SK, Hogan BM, Hall CJ, Torres-Vázquez J, Astin JW. Plexin D1 negatively regulates zebrafish lymphatic development. Development. 2022 Nov 1;149(21):dev200560. doi: 10.1242/dev.200560.

Eng TC, Chen W, Okuda KS, Misa JP, Padberg Y, Crosier KE, Crosier PS, Hall CJ, Schulte-Merker S, Hogan BM, Astin JW. Zebrafish facial lymphatics develop through sequential addition of venous and non-venous progenitors. EMBO Rep. 2019 May;20(5):e47079. doi: 10.15252/embr.201847079.

Project

In New Zealand, heart failure affects around 80,000 people. Patients living with heart failure have a poor quality of life because day to day tasks leave them breathless and incapacitated. There have been few new developments in management of heart failure in the last decade. Thus, there is a pressing and substantial unmet clinical need for improved treatment of heart failure.

We are currently investigating a novel heart pacing device which we have shown improves cardiac function in an ovine model of heart failure (1). We are particularly interested in how blood flow to the heart is altered during this intervention.

Autoregulatory behavior is the characteristic of a vascular bed to maintain blood flow constant in the face of changes in perfusion pressure. Coronary blood flow is autoregulated to help preserve perfusion to the myocardium despite changes in pressure. This summer studentship will characterize changes in coronary artery autoregulation in a normal and a preclinical animal model of heart failure.

This project will introduce the student to a number of experimental techniques including studies in conscious animals and data analysis from these studies. This will include aseptic surgery techniques (assisting with surgery), conducting experimental protocols in conscious animals and analysis of data. Preference will be given to students who would like to continue on with postgraduate study in the form of an Honors or a Masters project.

Skills that will be taught and mentored through this summer studentship include

• Literature review writing skills
• Collection of physiological data in conscious animals
• Analysis of data
• Oral presentation skills.

Reference

1. Reverse re-modelling chronic heart failure by reinstating heart rate variability.

Shanks J, Abukar Y, Lever NA, Pachen M, LeGrice IJ, Crossman DJ, Nogaret A, Paton JFR, Ramchandra R.

Basic Res Cardiol. 2022 Feb 1;117(1):4. doi: 10.1007/s00395-022-00911-0.

Become a Manaaki Manawa student researcher!

Our Manaaki Manawa summer research scholars will have the opportunity to become a part of the Manaaki Manawa Centre for Heart Research. Manaaki Manawa will provide:

• A welcome event for our summer scholars so that you have a chance to meet each other, learn about the Centre’s work, have some kai and meet the Centre team, including our Pou Tikanga
• Hot desks if you need a place to work and our Outreach and Education Lead, who will be available to support you
• A celebration at the end of the scholarships with students doing presentations or posters about their research
• Continued connection with Manaaki Manawa after your project ends, with opportunities to continue with some research if you are interested, with support from our team and researchers, and to participate in Manaaki Manawa events throughout the year.
  

Project

Metformin, a widely used treatment for type 2 diabetes, has recently been shown to have anti-inflammatory properties. Studies have shown that metformin blocks the inflammasome pathway, a key component of the innate immune system, in models of heart diseases and in inflammatory cells.

Recently, our team found that blocking the inflammasome pathway can protect against signs of cellular aging such as cellular senescence and epithelial-mesenchymal transition.

The aim of this study is to determine whether, by blocking the inflammasome pathway, metformin can protect against signs of cellular aging. To evaluate the study aim, the inflammasome pathway will be activated in retinal pigment epithelial cells using a combination of high glucose and pro-inflammatory cytokines. The cells will then be treated with a range of metformin doses for 24h. Using immunohistochemistry, cellular expression of inflammasome markers and cellular aging will be assessed.

The summer project will involve cell culture, immunohistochemistry, confocal microscopy, and image analysis.

Project

Extracellular accumulation of amyloid beta1-42 (Aß) is a key pathological process in Alzheimer’s Disease (AD). Although poorly recognised, AD involves neurodegeneration and microvascular alterations in both the brain and the retina. Endothelial cells that line blood vessels provide a critical dynamic barrier between the systemic circulation, brain, and retina. Aß has detrimental effects on vascular endothelial cell structure and function, contributing to the compromise of the blood-retinal- and blood-brain-barriers and consequently to pathology in AD.

Research from our lab has demonstrated the role of unregulated inflammation via the NLRP3 inflammasome pathway in various chronic retinal diseases. This pathway involves connexin 43 hemichannels, which open under pathological conditions. These channels pump out an ongoing supply of ATP that acts as an activation signal for the NLRP3 inflammasome and can lead to cell pyroptosis. This project aims to investigate the effects of aggregated amyloid beta1-42 peptide on human retinal microvascular endothelial cells, and if the NLRP3 inflammasome pathway is involved. This knowledge will help decipher the mechanisms of microvascular Aß-pathology and inform the therapeutic potential of targeting the inflammasome pathway in AD.

This project will treat human retinal microvascular endothelial cells with 20µM aggregated Aß1-42 for 24 hours and measure the amount of cell death using an LDH assay and the level of inflammasome specific markers (NLRP3 and cleaved caspase-1) using immunohistochemistry. If relevant, the cells will be treated with a connexin hemichannel blocker to determine the effect of modulating the NLRP3 inflammasome pathway on Aß-pathology.

The summer project will involve cell culture, immunohistochemistry, confocal microscopy, and image analysis.

Project

The use of magnetic resonance imaging (MRI) to evaluate the central lymphatic system has been increasing as an alternative to traditional invasive lymphangiography. Recent advances in magnetic resonance (MR) software and hardware have allowed for improved visualization of the of lymphatic system on MR and increasing options for less invasive management of disorders of the lymphatic system.

We are planning to investigate the lymphatic pressure in the thoracic duct.

Skills

• Literature review
• Cross-sectional anatomy
• Understanding biomechanics of lymphatics in thoracic duct.
  

Project

Immune checkpoint inhibitor (ICI)-mediated immunotherapy is emerging as a revolutionary therapeutic regimen for various cancer types but benefits only 10-40% of cancer patients. Their clinical response primarily relies on cytotoxic lymphocyte infiltration into solid tumours to recognise and kill cancer cells. However, abnormal solid tumour vasculature and dense stroma constitute a formidable physical barrier that strikingly limits lymphocyte infiltration and undermines their anticancer efficacy.

Our research aims to synthesise a series of lipophilic conjugates by linking nitric oxide (NO) donors with certain immunomodulatory drugs that are then loaded into a bioinspired therapeutic nanosystem (BNs). We will specifically develop these BNs to facilitate deep penetration and preferential accumulation of the active agent within solid tumours. The release of these agents can be triggered by intracellular glutathione (GSH) to efficiently remodel intricate physical tumour barriers, thereby improving lymphocyte infiltration and synergistically increasing the efficacy of immunotherapy in treating solid tumours.

This summer research project will focus on the synthesis of the NO-donor-drug conjugates (NDCs). The summer student will get well trained in medicinal chemistry and drug development, including skills in drug design, literature searching using databases (SciFinder, Reaxys etc.), organic synthesis, compound purification (chromatography, HPLC etc.), structure characterisation (NMR, MS etc.), drug assay and evaluation.

A fume hood in a standard chemistry laboratory, personal protective equipment, a desktop with necessary software and safety training will be provided. ACSRC has a multidisciplinary and collaborative environment.

Preferably, the candidate should have some experience in organic/organometallic synthesis.

Project

Allergic rhinitis and chronic rhinosinusitis are extremely common, chronic inflammatory conditions.

While the first line treatment is intranasal topical corticosteroids, usually by means of a nasal spray, there is limited study on the depth of penetration of the existing sprays and pharmacological preparations.

We aim to study both existing and novel therapies, and wish to develop a tissue penetration model. There are some established models in cornea explants, which may be adopt/adaptable to nasal tissue.

This study has a real clinical and therapeutic endpoint, which is always exciting.

Project

The infection of the front transparent part of the eye, the cornea, is one of the leading causes of permanent blindness worldwide. These infections are generally treated using broad-spectrum antibiotics. However, increasing antibiotic resistance has been identified as one of the main reasons for poor visual outcomes following a corneal infection.

To tackle this issue, we have been exploring the potential of novel light-based technology, a small dose of low-intensity ultraviolet c light (UVC), in managing such infections. Previous research has shown that high doses of UV and infrared light are associated with focal corneal opacities due to changes in protein dynamics. Although UVC can manage the infection with much lower doses than those implicated with loss of corneal transparency, its potential effect on corneal biophysics is unknown.

In this project, the successful applicant will investigate the effects of cumulative therapeutic UVC doses on corneal biomarkers, such as keratocytes and corneal DNA, to determine the upper safe dose in porcine corneas.

Techniques will involve immunohistochemistry, confocal microscopy, and image analysis.

Depending on time and student interest/skills, there may be further opportunities to expand areas of the project.

Project

We have been exploring novel light-based technology, low-intensity ultraviolet c light (UVC), for its potential to manage acute corneal infections. The determined therapeutic UVC dose has been shown to be safe in terms of DNA defects to both human-cultured corneal epithelial cells and animal corneas. However, UVC effects on healthy corneal nerves are still unknown.

The cornea is the most densely innervated tissue in the body, with a nerve density of 300–600 times that of the skin. Corneal nerves play an important role in the blink reflex, wound healing, and tear production and secretion. Therefore, any harmful effects on the corneal nerves interfere with corneal physiology and can devastate corneal health.

This summer project aims to examine the effects of UVC technology on healthy porcine corneal nerves.

Techniques will include immunohistochemistry, confocal microscopy, and image analysis to measure nerve density on the cornea before and after UVC exposure.

Depending on time and student interest/skills, there may be further opportunities to expand areas of the project.

Project

Heart failure is the inability of the heart to pump enough blood to supply the body’s energetic demands. A notable pathological feature of the failing heart is fibrosis, where excessive production of proteins, including collagen, fills the extra-cellular matrix (ECM). The ECM can be thought of as flexible scaffold that organises the cardiac myocytes into functional pump. At a macroscopic level fibrosis leads to both impaired relaxation and impaired contraction. However, limited data exists on the organisation of collagen at the nanoscale.

Recent data from the Cardiac Nanobiology Group demonstrates excessive production of the rarely studied type VI collagen appears to disrupt nanoscale intra-cellular organisation of the calcium signally apparatus that controls contraction.

In this project the successful applicant will use cutting edge super-resolution microscopy to characterise fibrosis and myocyte remodelling at the nanoscale. This will provide new insight on the structural changes that drive heart failure.

Project

Group A streptococcal (GAS) infections range from mild superficial infections (sore throats) to severe invasive infections. In humans, superficial infections can trigger the autoimmune disease acute rheumatic fever. There are currently no licensed vaccines to prevent these infections.

TeeVax is an experimental multivalent vaccine that incorporates alternating domains from T-antigen (a surface-exposed protein that forms the backbone of the GAS pilus) variants. It is based on 18 tee-types predicted to have over 95% coverage of strains circulating pre-2013. However, recent surveillance data have identified new variants that may not be covered by the vaccine (unpublished data).

The aim of this project is to assess vaccine coverage experimentally, thereby informing future vaccine design. This involves using molecular biology techniques to clone and express these new T-antigen variants coupled with serological techniques to determine the extent of antibody cross-reactivity from TeeVax-vaccinated animal sera.

There will be possibilities to extend work in this area towards an Honours, Masters, or PhD project.

Project

Oxygen deprivation around the time of birth can lead to brain injury in the infant, known as hypoxic-ischemic encephalopathy. The only treatment available for these babies is therapeutic hypothermia, which is the mild cooling of the head or whole body.

Although hypothermia has been shown to be effective in reducing the rate of death and disability in high income countries, this treatment is not recommended for babies born in low to middle income countries. Therefore, alternative treatments to hypothermia are needed for these babies.

A potential treatment is Exendin-4, which is a diabetes drug that has anti-inflammatory, anti-apoptotic and mitochondrial protective properties. We have investigated the effect of two different doses of Exendin-4 on near-term fetal sheep after hypoxia-ischemia.

This project will examine whether Exendin-4 (low dose or high dose) will have a neuroprotective effect by improving the survival of neurons and oligodendrocytes, improving myelination and reducing the proliferation of microglia. This will be assessed using immunohistochemistry and cell counting.

Skills learned during summer studentship

• Immunohistochemistry
• Microscopy
• Cell counting
• Statistical analysis
• Preparation of figures for publication

There are also potential honours projects available for suitable students in our lab group.

Project

Oxygen deprivation around the time of birth can lead to brain injury in the infant, known as hypoxic-ischemic encephalopathy. The only treatment available for these babies is therapeutic hypothermia, which is the mild cooling of the head or whole body. Although hypothermia has been shown to be effective in reducing the rate of death and disability in high income countries, this treatment is not recommended for babies born in low to middle income countries. Therefore, alternative treatments to hypothermia are needed for these babies.

A potential treatment is Exendin-4, which is a diabetes drug that has anti-inflammatory, anti-apoptotic and mitochondrial protective properties. We have investigated the effect of two different doses of Exendin-4 on near-term fetal sheep after hypoxia-ischemia.

This project will examine whether Exendin-4 (low dose and high dose) will improve the recovery of brain activity, reduce seizure burden and improve sleep state cycling. This will be assessed using custom-made physiological analysis software.

Skills learned during summer studentship

• Physiological analysis
• Seizure counting
• Sleep state cycling analysis
• Statistical analysis
• Preparation of figures for publication.

There are also potential honours projects available for suitable students in our lab group.

Project

Our lab is interested in using human umbilical stem cells in the treatment of eye disease by incorporating these cells into the diseased tissue and regenerating the damaged cells and tissues.

However, stem cells face several hurdles before tissue regeneration is possible - the cells must first survive, then migrate prior to integrating into the tissue and finally differentiating into the host cell phenotype.

This project will look at the reaction of implanting stem cells into ocular tissues and following the early fate of these cells in survival, migation, integration and differentiation.

Techniques will involve human tissue culture, microscopy, immunocyochemistry and PCR.

Project

Our lab has good evidence that female adult stem cells are more potent than male adult stem cells.

Is this a function of aging or is it a function of sex?

This project will look at female and male umbilical stem cells and ask if there are differences in potency at this very early stage.

Techniques will include human stem cell culture, microscopy, immunocytochemistry and PCR.

Project

Brain injury caused by reduced oxygen and blood flow to the brain (hypoxia-ischemia) is very common in preterm babies and has devastating consequences on neurological outcome. This pattern of brain injury typically involves damage to developing neuronal cells.

Our group has recently found evidence of damage to the brain regions that surround neurons (i.e., the extracellular matrix or ECM) following preterm brain injury. Further, this ECM damage seems important for controlling the survival of brain cells and the development of seizures. As part of a current series of experiments, critical evidence show that reducing injury to the ECM may be a novel treatment strategy to promote or restore brain function after preterm brain injury.

The aim of this preclinical study is to determine whether pharmacological blockade of abnormal ECM degradation is an effective therapeutic strategy to reduce neuronal damage following a hypoxic-ischemic insult. Specifically, we will investigate distinct sub-types of cortical/sub-cortical neurons, including gamma-aminobutyric acid (GABA)ergic interneurons that play a crucial role in neural network formation and brain development.

During this summer studentship, the successful applicant will be involved in the assessment of cell survival, neural connectivity, data analysis and basic statistics.

This research will provide new knowledge on the mechanism of preterm brain injury, and practical information on optimizing new interventions to improve outcomes for preterm babies at risk of brain injury.

Project

Newborn babies that suffer oxygen deprivation (i.e., hypoxia-ischemia) at birth are at high risk of death and lifelong neurological disability. Therapeutic hypothermia treatment (i.e., brain cooling) improves their survival and long-term outcomes, however, it is only partially effective. Moreover, recent evidence shows that chronic brain inflammation after hypothermia can exacerbate cerebral injury, and so contribute to long-term disability. Thus, the prognosis of these babies remains poor, and new neuroprotective treatments are needed. Recombinant erythropoietin (rEpo) is a pleiotropic hormone that protects brain cells and suppresses cerebral inflammation; however, it is not known whether it can improve long-term outcomes in these babies.

This project will investigate whether delayed rEpo treatment after brain cooling can enhance neuroprotection after hypoxia-ischemia, and so further reduce perinatal brain injury and neurodevelopmental disability in infants with neonatal encephalopathy.

For this summer studentship, physiological data analyses, immunohistology, microscopy and cell quantification will be used to determine neuronal and white matter survival, and degree of inflammation in the parasagittal cortex and subcortex after hypoxia-ischemia in term-equivalent fetal sheep, following either hypothermia alone or hypothermia plus delayed rEpo treatment. 

Skills and techniques taught during summer studentship

• Immunohistochemistry
• Bright-Field Microscopy
• Cellular quantification
• Computerized data analysis
• Graphing and statistical analysis.
  

Applications from candidates with Māori ancestry are encouraged.

If interested, please send your CV and academic transcript to arrange a chat about this project. 

Project

Perinatal oxygen deprivation (hypoxia-ischemia) at birth is a major contributor to death and disability in preterm babies. The predominant form of brain injury is diffuse, non-destructive lesions in the periventricular and surrounding white matter. To date, there are no proven therapeutics that can treat such brain injury in preterm infants. Catapres (clonidine hydrochloride), a a2-adrenergic agonist with potent anti-excitotoxic and anti-inflammatory properties, is a medication clinically used to treat high blood pressure and ADHD. In small and large animal studies, clonidine also reduced subcortical neuronal injury after hypoxic-ischemia; however, its therapeutic effect on white matter lesions is unknown.

The aim of this project is to determine whether clonidine can improve white matter injury after hypoxia-ischemia in the preterm brain.

For this summer studentship, immunohistochemistry, microscopy and cell quantification will be used to determine oligodendrocyte cell survival and inflammation in the preterm brain after hypoxia-ischemia, following treatment with either vehicle (control) or clonidine-hydrochloride.

Potential Honours projects are available for suitable candidates. 

Skills taught during summer studentship

• Immunohistochemistry
• Bright-Field Microscopy
• Cellular quantification
• Computerized data analysis
• Graphing and statistical analysis.
  

Applications from candidates with Māori ancestry are encouraged.

If interested, please send your CV and academic transcript to arrange a chat about this project.

Project

This study seeks to use pharmacometric methods to model the time-course of fever reduction after use of combined acetaminophen and ibuprofen therapy in children.

Data for modelling will be sourced from University of Bristol (Hay AD, Costelloe C, Redmond NM, Montgomery AA, Fletcher M, Hollinghurst S, Peters TJ. Paracetamol plus ibuprofen for the treatment of fever in children (PITCH): randomised controlled trial. BMJ. 2008).

This is a collaborative project between the Department of Anaesthesiology at the University of Auckland and the of Centre for Academic Primary Care, Bristol Medical School, United Kingdom.

The successful candidate will require an understanding of PKPD modelling and ability to use advanced computer programs such as NONMEM.

Similar data in a younger cohort of children is currently being collected by Prof Stuart Danziel (Cure Kids Prof Paediatrics).

Project

Aim: To conduct laboratory-based experiments to help understand the development and maturation of our peripheral hearing system.

Our sense of hearing is critical for daily communications and activities. Some early-onset hearing loss caused by congenital or secondary infection is known to manifest as bilateral hearing loss that is slowly progressive. The pathological mechanism is unknown; however, the involvement of inflammation has been suggested. This summer studentship project aims to characterize some features of the immature and developing cochlea.

The student will be trained to conduct lab-based work in the Department of Physiology to prepare tissue samples from animal models and study the histological and anatomical features of the immature cochlea by microscopy techniques.

The successful applicant will have strong interests in biology/physiology and in learning laboratory skills. Please feel free to enquire if you wish to find out more details on the project.

Skills learned during summer studentship

• Tissue dissection
• Tissue sectioning
• Immunohistochemistry
• Fluorescent microscopy
• Image processing
• Report writing
• Literature search.
  

Project

Aim: To conduct laboratory-based experiments to help understand the cellular features in the temporal bone that houses our peripheral hearing system.

Our sense of hearing originates in the inner ear organ called the cochlea. Cochlea is a pea-sized organ taking shape similar to a snail shell, containing complex networks of vasculatures, innervations, sensory cells, and neurons. The entire cochlea is encapsulated in the dense temporal bone of the skull.

To better understand the complex tissue physiology within the cochlea, this summer studentship project aims to characterise cellular features in particular segments of the temporal bone.

The student will be trained to conduct lab-based work in the Department of Physiology to prepare tissue samples from animal models and study features of the temporal bone by microscopy technique.

The successful applicant will have strong interests in biology/physiology and have keen eyes for anatomy and in learning new skills. Please feel free to enquire if you wish to find out more details on the project.

Skills learned during summer studentship

• Tissue dissection
• Tissue sectioning
• Immunohistochemistry
• Fluorescent microscopy
• Image processing
• Report writing
• Literature search.
  

Project

Pancreatic beta cells secrete the hormone insulin, which is crucial for blood glucose regulation. The mechanisms regulating insulin secretion are very complex and are not fully elucidated. Despite extensive research, our basic knowledge of many processes involved in ß-cell function is limited, making it harder to develop more targeted and optimized treatments for type-2 diabetes.

We have made significant discoveries uncovering crucial roles of adherens junction protein in insulin secretion. Here, we found that all the components of adherens junctions, including beta-catenin, Alpha-catenin, p120catenin, cadherins and plakoglobin have unique roles in the modulation of insulin release. Now we are aiming to understand the mechanism by which how adherens proteins modulate insulin release.

This summer project will focus on understanding how the interactions and localization of adherens junction proteins are modulated by extracellular stimuli during the regulation of insulin secretion.

The students will be able to learn cell culture techniques, western blotting, cell fractionation, and immunoprecipitation(protein-protein interactions) assays during the training.

Project

Precision oncology strives to improve the outcomes for cancer patients by tailoring treatment to the underlying biology of their tumour. Underpinning precision oncology is a strong basic biology foundation, with a robust mechanistic understanding of the effects of genetic changes. However, up to 40% of the genomic alterations found in cancer are variants of uncertain significance (VUS) for which no published data exists on their mechanism of action or oncogenicity. This lack of knowledge hinders proper evaluation of variants and is an unmet need that impacts on the ability of oncologists to make informed decisions on patient treatment.

This proposal aims to provide a functional rationale for the reclassification of VUS identified in cancer patients in New Zealand by understanding their cellular consequences. The genes involved will either by receptor tyrosine kinases or mismatch repair genes.

The student will be embedded within a research group with experts on genomics and cell and molecular biology working alongside clinicians.

Techniques covered will include cell culture, cell growth assays, qPCR and Western blotting. CRISPR/Cas9 genome editing may also be used to generate gene knockouts.

Project

The cGAS-STING pathway drives activation of type I interferons and other inflammatory cytokines, playing a key role in the host immune response against tumours. Several STING agonists have shown anti-tumour efficacy in pre-clinical studies and are in clinical development, however systemic administration of these compounds can pose safety issues and intratumoural injection is limited by tumour accessibility.

The non-pathogenic bacterium Clostridium sporogenes, upon injection as inert spores, can germinate into active bacteria in necrotic tumour regions, resulting in a tumour-specific bacterial infection.

In this project, you will investigate whether C. sporogenes can activate the cGAS-STING pathway in human and mouse antigen-presenting cells, towards a goal of overcoming the delivery challenges associated with other STING agonists.

Techniques may include cell culture, microbiology in a PC2 laboratory, enzyme-linked immunosorbent assay (ELISA), flow cytometry, and PCR.

Project

Most medical therapies only help a subset of the patients. For many medications, these inter-individual differences are due to at least partially genetic variations. A tailored approach to medicine is needed to be able to fundamentally change the way how we treat patients.

Emerging evidence polymorphism in drug transporter genes influence the efficacy and toxicity of numerous drugs. We have identified several Māori and Pacific specific drug transporter variants which are very rare in the rest of the world and thus have yet been studied.

In this project, we will test the transport of a wide range of clinical drugs which can be transported by these transporters and examine the subsequent functional alterations.

Techniques will include: Culture of mammalian cells; gene over-expression; western blot; inductively coupled plasma mass spectrometry; LC-MS; ELISA assay; data analysis and presentation skills.

Project

Evolution has produced a myriad of adaptations allowing animals to thrive in extreme conditions such as in hypoxia. These changes range from the generation of endogenous carbon monoxide to down-regulate mitochondrial oxygen requirements during hypoxic dives, to haemoglobin mutations, novel tissue oxygen storage methods and localised cooling. Some of these mechanisms are already being applied clinically to improve human health. An example is the use of carbon monoxide (usually considered a poison) and cooling in organ transplantation and stroke. These reduce immediate oxygen requirements and this prevents acute cell death.

We are only just starting to tap the huge potential of this scientific resource. By using evolved mechanisms "perfected" by millions of years of evolution will provide a shortcut to designing protective mechanisms that can be relatively easily adapted for human health.

The summer project will involve the processing of imaging data from one of these hypoxia-tolerant species (possibly dolphin brain MRI).

Skills required: Attention to detail and an inquisitive mind.

Skills to be learnt: Neuroanatomy. 3D image data processing and segmentation. If progress is good, manuscript preparation for publication.

Project

To improve the selectivity for cancer cells and minimise toxicity to normal healthy cells we synthesised novel prodrugs of potent anticancer agents. These compounds were designed to be excluded from cells and rapidly excreted from the body. However, we found that our prodrugs are surprisingly effective at killing some cancer cell lines in culture at very low concentrations. Given that the prodrugs carry a negative charge, our hypothesis is that transporters on the cell membrane mediate active transport of the prodrugs into the cells. Based on gene expression of possible transporters in a publicly available database we have identified two likely candidates for the responsible transporters.

In this project we will look at cell killing by drug/prodrug pairs in cell cultures with a small panel of human cancer cell lines that span a range of gene expression levels of these two transporters. Correlation analysis will be the first step to test our hypothesis. In addition, we will investigate if reported inhibitors of the transporters can modulate the cytotoxic potency of the prodrugs.

The results will guide the design of other prodrugs of the same class for chemical synthesis and subsequent assays in cell cultures. The ultimate goal is to develop a novel anticancer agent along with an understanding of the features (biomarkers) that control its activity.

Project

The marine carotenoid Astaxanthin (ATX) exhibits potent antioxidant and anti-inflammatory properties at the cellular level. Diabetic retinopathy, which involves tissue inflammation and oxidative stress damage, can have severe and permanent effects on vision. This condition is disproportionately over-represented among the Māori and Pacifica populations in Aotearoa/New Zealand.

In recent in-vitro studies conducted on C57BL/6 mouse retinal tissue, where we modelled diabetic conditions of the retina, we observed that the presence of ATX in the diabetic environment resulted in a statistically significant reduction of propidium iodide staining in the various layers of the choroid, photoreceptors, and notably, the retinal pigment epithelium (RPE) cells that support the photoreceptors in the retina.

Building upon these findings, our current in vitro investigation aims to study the effect of ATX on specific biochemical markers known to undergo changes in the diabetic retina, such as ATP, lactate, Glyceraldehyde 3-phosphate dehydrogenase (GAPDH). Additionally, we will assess the effects of ATX on neurotransmitter levels, including glutamate and glycine.

These investigations are required to better understand the protective mechanisms associated with ATX, thereby paving the way for effective in vivo mouse studies in the future.

Project

Glioblastoma (GBM) is the most common and fatal primary brain tumour in adults, with a median survival time of only 16 months. The lack of curative therapies is partly attributed to the highly heterogeneous nature of GBM tumours with multiple tumour subtypes and various intra-tumoural microenvironments (TMEs) that complicates diagnosis and treatment design. Therefore, a crucial step in advancing GBM treatments is to elucidate and model GBM’s inter- and intra-tumour heterogeneity. Some progress has been made through multi-omics approaches, enabling the reclassification of GBM into prognostically relevant molecular subtypes. However, these techniques lack the protein-based validations and the anatomical context that are required for the accurate diagnosis of GBM.

Therefore, this summer studentship aims to use multiplex immunohistochemical techniques to elucidate prognostically relevant protein expression on tumour cell types that comprise the various GBM TMEs. This information will be modelled onto an H&E stain of brain tumours using deep learning to develop a histology-based predictive model for high-grade brain tumours.

The successful applicant will learn how to work with human brain tumour specimens, undergo multiplex immunohistochemistry techniques, operate automated microscopy, and use machine learning to correlate protein expression with clinical outcomes.

Project

For over 60 years, antibiotics have been crucial in modern medicine, curing infectious diseases and preventing infections in immunocompromised individuals. However, their overuse has led to an alarming increase in antibiotic-resistant bacteria, creating a need for new antibiotics with different mechanisms of action.

One promising avenue to discovering new antibacterial compounds is exploring natural products in the form of fungal secondary metabolites. Fungi produce various unique secondary metabolites utilising a small set of precursor molecules as building blocks. Precursor-directed biosynthesis (PDB) is an approach that introduces non-natural precursor molecules into the growth medium of microorganisms to produce modified metabolites with unique biological activities. PDB has significant potential offering valuable insights into industrial applications such as medicine, agriculture, and other fields.

Knowledge of microbiology and biochemistry is preferred.

Project

Magnetic resonance imaging (MRI) is a versatile imaging modality widely employed in biomedical research and clinical diagnosis. However, its use for imaging small samples is limited due to the low accessibility and high cost associated with clinical MRI machines. Fortunately, the innovative "ilumar" system has emerged as the world's first desktop MRI, designed for operation in any laboratory environment with ease: https://www.resonint.com/products

This project aims to thoroughly investigate the feasibility of the ilumar system in the field of biomedical research. We will develop and optimise imaging protocols for ilumar, utilizing diverse samples such as chemicals and tissues, and compare the obtained results with those acquired using the clinical 3T MRI. By doing so, this project aims to provide valuable guidance to researchers within the broader scientific community regarding the utilization of this system.

Throughout this project, the successful applicant will have the opportunity to:

• Develop a profound understanding of MRI fundamentals
• Acquire valuable experience in MRI acquisition, optimisation, and analysis
• Cultivate essential laboratory skills required for the preparation of testing tissues and samples.
  

Project

Like many other tissues, the eyes undergo age-related changes, making them susceptible to various eye diseases. These physiological alterations in ocular tissues necessitate investigation.

Multi-parametric mapping, an MRI-based technology, offers the ability to extract quantitative information from tissues. In our laboratory, we have successfully established MRI protocols and post-processing tools to assess the free and bound water content of the crystalline lens in-vivo, which serve as crucial biomarkers for lens physiology.

This project aims to expand our analysis to other ocular tissues, including the vitreous, optic nerves, and extraocular muscles. By leveraging our existing data, we will investigate the underlying age-related changes in these tissues.

Throughout this project, the successful applicant will have the opportunity to gain experience and develop skills in the following areas:

• Eye anatomy and physiology
• A comprehensive understanding of MRI fundamentals
• Valuable hands-on experience in MRI acquisitions and post-processing techniques using MATLAB
  

Please note that although proficiency in MATLAB is required for the analysis in this project, training will be provided for those who need it.

Project

Our lab is studying the T44M variant in the SLC22A3 gene which has been reported to be present in 14% of Māori and Pacific people but rare in other populations. SLC22A3 encodes the OCT3 protein which has a crucial role in transporting positively charged drugs into cells.

We have shown this gene variant greatly increases the rate at which OCT3 transports the commonly used anti-diabetic drug metformin. We also show this affects the pharmacology of metformin in such a way that it is likely to make metformin ineffective. SLC22A3 also transports a wide range of other commonly used medications including some used to treat heart disease and cancer.

This project will explore whether or not this genetic variant also affects the transport and pharmacology of such drugs.

Project

BRAF inhibitors achieve short term effects in many tumours that are driven by mutations in the BRAF gene but these effects are short lived. Our recent studies have shown that adding an inhibitor of VEGFR2 can greatly increase the efficacy of this treatment in ways that can be synergistic.

This project will undertake molecular analysis of tumours after such treatment to look for the mechanisms involved in the synergies.

Project

Pulmonary arterial hypertension (PAH) is a severe condition that leads to relentless progressive increases in pulmonary artery pressure, eventually developing into right heart failure and premature death. Despite current treatments, exertional dyspnoea and exercise limitation remain debilitating problems for people with PAH, but the current understanding of the underpinning physiologic drivers of this are incompletely understood.

In order to find new treatment pathways, we are examining novel autonomic physiologic drivers of exertional dyspnoea in PAH, such as skeletal muscle afferents and chemoreflexes, through physiologic experiments involving both people with PAH and healthy people.

The purpose of this project is to establish new methods of examining the control of breathing and the cardiovascular system at the University of Auckland, that can be applied to a clinical population.

Skills

• Working with human volunteer study participants
• Data analysis
• Presentation skills 
• Academic writing.

Become Manaaki Manawa student researcher

Our Manaaki Manawa summer research scholars will have the opportunity to become a part of the Manaaki Manawa Centre for Heart Research. Manaaki Manawa will provide:

• A welcome event for our summer scholars so that you have a chance to meet each other, learn about the Centre’s work, have some kai and meet the Centre team, including our Pou Tikanga
• Hot desks if you need a place to work and our Outreach and Education Lead, who will be available to support you
• A celebration at the end of the scholarships with students doing presentations or posters about their research
• Continued connection with Manaaki Manawa after your project ends, with opportunities to continue with some research if you are interested, with support from our team and researchers, and to participate in Manaaki Manawa events throughout the year.

Project

Alzheimer’s disease (AD) is the most common neurodegenerative disorder, affecting around 10% of people over 65 years old worldwide. AD results in significantly reduced quality of life for individuals, alongside substantial whanau, societal and economic burden.

Our understanding of AD pathogenesis is incomplete. However, genetic and functional evidence points to microglia as key players in this disease. Microglia are the resident immune cells of the brain. They are flexible cells and can take on many forms and functions. Microglia are involved in Aß plaque clearance and neuroinflammation. A recent study from our lab reports the up-regulation of novel genes in microglia in AD.

The aim of this project is to investigate protein-level changes in the newly-discovered microglial protein GPNMB, using human cells and tissue.

This research will provide valuable new knowledge aimed at understanding microglial involvement in AD and treatment of this disorder.

You will be part of a research team including other post-graduate students working towards a common goal of better understanding of the brain’s immune system to discover novel treatments for brain disorders.

Skills

• Immunocytochemistry
• Immunohistochemistry
• ELISA
• High-throughput microscopy
• Image analysis.

This project will use a range of protein-based assays to measure key microglial proteins in human brain cells and tissue. You will perform data analysis, interpretation of results and review of relevant scientific literature – which may form the basis of a literature review publication.

Project

Babies born prematurely are at a high risk of developing brain injury and neurological impairments such as cerebral palsy, learning and cognition problems, and behavioural difficulties. Currently, no standard treatments are available to protect and repair the preterm brain. Oxygen deprivation and reduced brain blood flow before or during birth is a major cause of preterm brain injury, and most injury evolves well after the initial insult over weeks to months.

We now understand that chronic inflammation is a key mediator in the delayed evolution of injury and impaired brain maturation.

During this summer studentship project, the student will examine whether targeting inflammation with glucagon-like peptide (GLP) 1 analogue after acute oxygen deprivation in preterm fetal sheep reduces neuro-inflammation, attenuates grey and white matter injury, and improves white matter maturation.

The student will master highly transferable skills, including immunohistochemistry, microscopy, image analysis, cell quantification and statistical analysis.

The findings from these studies will inform future pre-clinical and clinical studies of potential therapies and thus contribute to improving the long-term outcomes of preterm infants.

Skills

• Immunohistochemistry
• Microscopy
• Image analysis
• Cell quantification
• Statistical analysis.
  

Project

Epidemiological evidence shows that women whom suffered from preeclampsia (a hypertensive disorder) during pregnancy are at 3.5-fold risk of developing early vascular dementia later in life. Our previous work shows that placental extracellular vesicles (EVs) derived from the syncytiotrophoblast, the largest single cell in the body, can carry cargo capable of damaging maternal blood vessels in the systemic vasculature. We hypothesized that perhaps these placental EVs also damage the vasculature in the brain and may lead to leaky blood vessels that precede the development of dementia.

We have access to brain tissues from an experimental model of preeclampsia where rats were injected with placental EVs from preeclamptic pregnancies.

In this project, we will use histological techniques to assess the integrity of the blood brain barrier in animals injected with placental EVs, and control animals.

Project

Recent evidence suggests that in humans, the outcome of pregnancy is associated with mum’s long term cardiovascular health. Women who experience preeclampsia (a hypertensive disorder) during pregnancy are at a higher risk of developing cardiovascular disease later in life – a risk higher than that imposed than smoking! Conversely, women whom have had healthy pregnancies appear to be protected against developing cardiovascular disease. We think that the link between the outcome of pregnancy and future cardiovascular disease lies in the nature of placental extracellular vesicles.

Placental extracellular vesicles (EV) act as long distance fetal-maternal communicators during pregnancy. We have shown that these EVs contain cargo that can damage maternal blood vessels leading to a pro-vasoconstrictive phenotype after 24 hours in rodents. We want to know whether this damage is retained long term in rats, and whether this translates to a higher blood pressure and poor cardiac function as seen in women.

During this project, the student will experience working in a lab using state-of-the-art ultrasound to assess cardiac function and non-invasive blood pressure measurements for long term cardiovascular monitoring. It will also involve analysis of previously collected data from this long term project.

Project

Mild traumatic brain injury (mTBI, e.g. concussion) has recently received media attention, especially for athletes in contact sport. The significance of mTBI is well accepted, however the detailed pathophysiology of the impact and associated symptoms is still under investigation. Researching mTBI is further complicated by difficulties in both data collection and experimentation due to large variability in the sustained injury and subsequent symptomology. A virtual brain model can address this problem as a simulation based on MRI scanned geometry can establish a framework to predict areas of high stress concentration for a particular impact.

This project will build on a pre-existing large human MRI database, collected over multiple seasons of rugby.

There are two major parts:

1. To perform a manual segmentation of the brain, including the skull and different white matter tracts
2. Use the segmented geometry from the first part, run a simulation of the impact, and run correlation tests with cognitive testing and instrumented mouthguard data.

Once the simulation has been validated to replicate the injury truthfully, this will serve as a significant foundation to the next phase of the project: the human mTBI simulation.

All software and simulation training will be provided.

Project

The brain floats inside the cranium, supported by cerebrospinal fluid (CSF).

The blood pulsation, coupled with the CSF motion, induces time-varying pressure on the brain parenchyma. The pulsatile movement of the brain can provide important material property parameters that can distinguish between healthy and diseased states non-invasively.

The brain is generally assumed to be incompressible, however, due to interstitial fluid volume and structural organisation, different regions can move relative to each other by a small amount. These movements are concentrated around the brainstem and diencephalon area. Amplified MRI (aMRI) allows enhanced visualisation of these subtle movements which will have significant clinical relevance as a non-invasive tool to assess changes in brain material properties.

The goal of this project is to investigate the relationship between CSF flow, blood pulsation, and associated aMRI motion changes in a healthy subject. The gold standard flow analysis tool such as ultrasound Doppler and phase contrast MRI will be used to quantify the flows of CSF and blood.

An expected outcome of the project is a physiological explanation of changes in observed aMRI motion based on the CSF and blood volume changes.

We are looking for a student with an interest in brain imaging and post-processing, including 4D flow. The project will provide an exciting opportunity to work within a large multidisciplinary team, involving both medical imaging and bioengineering.

Project

Aims: During coronary artery bypass graft surgery (CABG), surgeons often find it difficult to accurately measure the length of saphenous vein graft (SVG) conduit required, particularly for grafts arising from the aorta to the right coronary artery (RCA) system.If a graft is too long then there may be less blood flow due to increased resistance and the graft is susceptible to kinking. Moreover, the wound from the vein harvest in the lower limb is unnecessarily longer than it need be.

In this study, the flaccid versus pressurized radius and length of saphenous vein conduits will be investigated. CT coronary angiogram scans will be analysed of patients who have undergone CABG with SVG to RCA.

The information will be processed using a novel 1D-0D computational fluid dynamics model called “COMCAB” which has scope for improvements. The suitable length of venous conduit required to be harvested will then be determined based on predicted graft pressures and lengths.

Skills

• Record measurements taken intraoperatively by surgeons
• A background in Python coding is desirable but not essential
  
• At the conclusion of the research project, with the help of supervisors, the student should write a manuscript for peer-review publication and deliver an oral presentation at a local or international conference.

Project

Acute rheumatic fever is a serious post-immune sequel of an infection with Group A Streptococcus (Strep A). The pathogenesis of rheumatic fever remains poorly understood, yet it can lead to chronic rheumatic heart disease that is associated with significant morbidity and mortality both locally in Aotearoa New Zealand and globally. Mast cells are considered innate immune cells and act as initial responders to many microbial infections. They have a key role in allergic reactions, but are increasingly being recognized as also contributing to autoimmune disease by causing tissue destruction and symptoms at target sites.

This project will explore whether mast cells have a role in rheumatic fever. Key mast cell mediators (Chymase and Tryptase) will be measured in sera from patients with rheumatic fever, and compared to levels in patients with uncomplicated strep A infections and healthy controls.

This data will be integrated with other clinical and immune data for the cohort to provide insight into mast cell activity in rheumatic fever.

Project

Targeted MRI (also known as MASDIR) sequences are a new MRI technique that uses old-school inversion recovery sequences in a new way. By creatively adding, subtracting, multiplying, and dividing images obtained using different inversion time, one can create images both exquisitely sensitive to small changes in T1 and synergistically sensitive to changes in T1, T2, and diffusion coefficient.

Targeted MRI is well-poised to show subtle changes in T1 within the brain, for example, due to neuroinflammation.

As neuroinflammation is associated with multiple neurodegenerative diseases (e.g. Alzheimer's) and injuries, an increased resolution to detect neuroinflammation will allow earlier intervention and potentially a better outcome.

We will be investigating the use of targeted MRI sequences to see if they can increase the diagnostic performance of MRI.

The successful applicant will help with targeted MRI image creation, radiology-pathology correlation, and assessment of the new sequence’s performance.

Skills

• MATLAB
• Image processing
• Data analysis.
  

Project

Amplified MRI (aMRI) is a new imaging method that magnifies very small motion of the brain as the heart beats. The aMRI method takes a standard dynamically resolved MRI sequence (available on all scanners to-date), and produces an amplified movie of brain motion: https://www.youtube.com/watch?v=m9pGG9zh2yk

This approach reveals deformations of the brain parenchyma and displacements of arteries due to cardiac pulsatility, especially in the brainstem, cerebellum, and spinal cord, which have not been observed before.

The method has shown early promise for detecting pathological brain motion due to diseases or disorders that obstruct the brain or block the flow of cerebrospinal fluid, such as in Chiari Malformation I (CMI) patients.

The project aims to enhance our knowledge about the link between obstructive brain disorders and brain motion.

Skills

• MATLAB
• Image processing
• Biomechanical modeling
• Data analysis.
  

Project

Immunotherapy has revolutionised cancer care. By stimulating the innate ability of the patient’s immune cells to fight cancer cells, immunotherapy can cure cancer. Yet, this does not happen in most patients because cancers sabotage their immunity. Most cancer types produce a tryptophan metabolite called kynurenine that paralyses cancer-killing immune cells and undermines immunotherapies. To make more patients benefit from immunotherapies, kynurenine production needs to be stopped.

This research programme investigates the immunosuppressive tryptophan catabolism in cancer and tests innovative strategies for arresting kynurenine production. We hope to eventually translate these new strategies into therapies for use as immunotherapy sensitisers in the clinic.

This research is highly multidisciplinary and blends aspects of chemical, cell and molecular biology, and ventures into exciting uncharted territories offering something to any curious mind.

The stage of the research programme at the given time and the student’s interests will determine the specific research question for this summer project.

Project

Gestational diabetes (GDM) is one of the most common complications associated with pregnancy and it has a direct impact on the future cardio-metabolic health of the mother and the child. Cardiovascular and metabolic diseases are responsible for most of the gap in life expectancy and are associated with higher hospitalisation and mortality rates for Māori and Pacific people in Aoteoroa New Zealand. The age of onset of cardio-metabolic conditions is also significantly younger in Māori and Pasifika than in other New Zealanders and the incidence of these conditions continues to increase. While early detection and intervention of GDM can substantially reduce adverse outcomes for mothers and babies, several studies have reported inequities in screening, diagnosis and management of GDM between Māori, Pasifika and other women.

There is an urgent need for qualitative data that not only provides rich and meaningful information, but can also be a powerful tool for change and to inform the development and implementation of effective interventions.

We have several small projects that include data analysis, community engagement using co-design methodologies; all with the aim of developing a co-designed targeted framework that will significantly improve the GDM screening and post-partum follow up rates among marginalised communities.

Become Manaaki Manawa student researcher!

Our Manaaki Manawa summer research scholars will have the opportunity to become a part of the Manaaki Manawa Centre for Heart Research. Manaaki Manawa will provide:

• a welcome event for our summer scholars so that you have a chance to meet each other, learn about the Centre’s work, have some kai and meet the Centre team, including our Pou Tikanga.
  
• hot desks if you need a place to work and our Outreach and Education Lead, who will be available to support you
• a celebration at the end of the scholarships with students doing presentations or posters about their research
  
• continued connection with Manaaki Manawa after your project ends, with opportunities to continue with some research if you are interested, with support from our team and researchers, and to participate in Manaaki Manawa events throughout the year.

There are also two Manaaki Manawa scholarships open to Māori, Pacific or women students, that have a $2,000 supplement in addition to the standard scholarship.

Project

Antibiotic resistance has been recognised by the WHO as one of the greatest threats to humanity and infectious diseases rank as the second most common cause of death worldwide. New antibiotics are desperately needed and if nothing is done by 2050 it is estimated > 10M people will die per annum, which is more that cancer and diabetes.

Cyclic lipopeptides are an emerging subset of peptide-based antibiotics (e.g., FDA-approved daptomycin and polymyxin) containing a lipid or fatty acid. They have been shown to possess clinical efficacy and are used as the “last line of defence” against otherwise untreatable bacterial infections. Despite their promise, undesired toxicity is a significant drawback

We are developing novel, non-toxic derivatives of naturally occurring lipopeptide antibiotics (e.g., Fig. 1) by modifying the chemistry of the lipid tail. Novel antibiotic analogues will undergo biological testing against multi-drug resistant (MRD) strains of bacteria and evaluation of potential toxicity.

Successful candidates will use organic synthesis and modern methods of solid phase peptide synthesis. Candidates will also have the opportunity to undertake and learn biological assays if they desire.

References

See: Harris et al. ACS Infect. Dis. 2022, 8, 2413
See: Sarojini et al. J. Med. Chem. 2015, 58, 2, 625