Biomedical Science
Applications for 2024-2025 open 1 July 2024
Investigating the impact of circulation on lymphatic biomechanics using MR
Project code: MHS008
Supervisor:
Discipline: Biomedical Science
Project
Performing literature review
Learning lymphatics anatomy
Learning cardiac and lymphatics physiology
Learning MR imaging
Can we prevent white matter injury after mild oxygen deprivation at birth?
Project code: MHS009
Supervisor:
Discipline: Biomedical Science
Project
There is increasing evidence that mild oxygen deprivation at the time of birth is associated with poor neurodevelopmental outcomes, including brain injury, behavioural issues and autism. In particular, recent evidence suggests that infants with mild oxygen deprivation have extensive injury within the white matter of the brain, which has been associated with long-term disability. Concerningly, there are currently no available treatment options for infants that have had mild oxygen deprivation.
Role
We have conducted a pre-clinical study in term-equivalent fetal sheep to investigate the two leading treatment options – therapeutic hypothermia and erythropoietin. This summer studentship will determine whether hypothermia and erythropoietin reduce injury to the white matter tracts after mild oxygen deprivation, including assessing survival of oligodendrocytes and integrity of myelin. This summer studentship will involve microscopy, immunohistochemistry and image analysis.
This study is the first to specifically investigate treatment strategies for mild oxygen deprivation in a large animal translatable model. The results of this studentship will provide valuable insight into how best to treat infants that have had mild oxygen deprivation.
Please contact us for more information on this summer studentship or to find out more on potential honours and masters projects that we have available
Skills learned:
Immunohistochemistry
Microscopy
Data analysis
Statistical analysis
Targeting leukaemia at its roots, the leukaemia stem cells
Project code: MHS010
Supervisor:
Discipline: Biomedical Science
Project
Every day 8 people in NZ 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.
Role
The summer student will be embedded within a research group with experts on leukemia genetics, next generation sequence analysis and animal models of leukaemia.
Skills learned
Being exposed to this project will be an opportunity for the summer 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.
Assessing mitochondrial function in cultured beating heart muscles
Project code: MHS011
Supervisor:
Discipline: Biomedical Science
Project
Cardiovascular disease is the number one cause of death in New Zealand and better drugs are required to improve treatment options. Furthermore, the heart is subject to off target effects of drugs that are highly effective for treating chronic diseases such as cancer and psychotic disorders. Understanding the cellular mechanisms of cardiac dysfunction will enable better treatment and reduce side effects of non-cardiovascular medications.
Most pre-clinical research is proven in animal models, but often fails in humans. Our research group has established a human heart tissue culture system to study the contractility of beating heart tissue over days-to-weeks to enable long-term study of isolated human heart tissue. Following informed consent, right atrial appendage samples are collected from patients undergoing cardiac surgery. From this sample small atrial muscles are dissected and mounted in a muscle chamber, connected to a MyoDish tissue culture system, and stimulated to contract.
Role
This project will assess mitochondria function using high-resolution respirometry in tissue samples at different time points during the culture protocol to establish any baseline changes that are important to characterise in this exciting new experimental model.
Skills learned:
• Microdissection
• Tissue culture
• Muscle function testing
• High-resolution respirometry
• Data analysis
• Scientific writing
Quantifying coenzyme Q10 levels in human heart tissue
Project code: MHS012
Supervisor:
Discipline:
Biomedical Science
Project
Type 2 diabetes (T2D) is one of the largest and fastest growing health issues within New Zealand and is closely linked with the development and progression of cardiovascular diseases, including heart failure. Research from our laboratory has demonstrated a deficit in mitochondrial energy production in atrial tissue from diabetic hearts.
Diabetic patients are often prescribed statins to lower their risk of developing heart disease. While statins are an important preventative medicine for heart disease, their mechanism of action leads to a decrease in circulating coenzyme Q10 (CoQ10). CoQ10 is vital for mitochondrial energy production, particularly in the heart, which relies on mitochondria for 95% of its energy. A potential side-effect of long-term statin use is a decrease in CoQ10 in the heart which could contribute to impaired energy supply.
Role
Both T2D and statin use independently decrease plasma CoQ10 levels in clinical studies, however, it is not known if tissue levels of CoQ10 in the human diabetic heart are also affected. This project will utilise stored human heart samples from diabetic and non-diabetic patients to quantify the levels of CoQ10 and mitochondrial protein using high-performance liquid chromatography and protein assays.
Skills learned
• Mitochondrial isolation
• High-performance liquid chromatography
• Data analysis
• Scientific writing
Can an Anti-Inflammatory Prevent Cortical Injury after Hypoxia-ischemia? A Pre-clinical Study
Project code: MHS019
Supervisor:
Discipline: Biomedical Science
Project
Preterm birth is strongly associated with neonatal death, brain injury and impaired development, which underpins life-long neurodevelopmental disability. It has become clear that severe brain injury caused by reduced oxygen and blood flow to the brain (hypoxia-ischemia) develops over a long period of time, with cystic brain injury only becoming apparent 2-3 weeks after birth. These cystic lesions are the greatest risk factor for cerebral palsy, and unfortunately, there are no established therapies available.
Using an animal model, our group has investigated a powerful anti-inflammatory drug (Etanercept) as a potential treatment. We have shown that giving etanercept 3 days after hypoxia-ischemia can prevent severe white matter injury (See https://shorturl.at/QxIb7). Overall, this study offers hope that substantial protection may be possible in babies with preterm brain injury with even very delayed treatment strategies.
Role
We have yet to investigate whether etanercept can treat cortical and thalamic structures, which are also commonly injured by hypoxia-ischemia. Therefore, during this summer studentship, the successful applicant will be involved in the pathological assessment of brain injury and development in brain slices using immunohistochemistry and microscopy.
This research will expand our understanding of strategies to improve outcomes for preterm babies at risk of brain injury.
Targeting sympathetic nerve activity to stop cardiac arrhythmias - this project has been withdrawn
Project code: MHS022
Discipline: Biomedical Science
Project MHS022 has been withdrawn
DNA encoded libraries for the drug discovery of tomorrow
Project code: MHS025
Supervisor:
Discipline: Biomedical Science
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 has recently emerged to address this challenge. DELs are pooled binding assays that can be used to screen ultra-large collections of compounds (billions) 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.
Role
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 UoA for the first time.
Skills learned
The student will gain exposure to the design, chemoinformatic analysis, synthesis and mass spectrometry analysis of DNA encoded compound libraries for drug screening.
Finding molecular connections between gestational diabetes and heart disease
Project code: MHS029
Supervisor:
Discipline: Biomedical Science
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.
Role
We have several small projects that include data analysis and community engagement using co-design methodologies – all with the aim goal of developing a co-designed targeted framework that will significantly improve the GDM screening and post-partum follow up rates among marginalised communities.
Gestational Diabetes
Project code: MHS030
Supervisor:
Discipline: Biomedical Science
Project
Cardiovascular disease (CVD) is the single biggest killer of women in New Zealand. Evidence strongly indicates that gestational diabetes (GDM, diabetes during pregnancy) contributes to the global diabetes epidemic. 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. Reducing CB activity has been shown to be beneficial for cardio-metabolic health.
Role
Understanding how CB activity changes during pregnancy and how it could contribute to GDM in the mother and cardio-metabolic disease in her and her offspring 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.
Tinder for proteins – using induced proximity to bring proteins together, reprogramme their function, and treat cancer
Project code: MHS032
Supervisor:
Discipline: Biomedical Science
Project
Proximity-inducing drugs are an emerging innovation in pharmaceutical development. This concept employs heterobifunctional molecules that are designed to bring two different proteins into close proximity to reprogramme their biological functions.
Role
In this project we seek to generate a novel series of transcriptional/epigenetic chemical inducers of proximity (TCIPs). TCIPs work by recruiting epigenetic remodelling complexes to sites in the chromatin that are bound by oncogenic transcription factors. Once located at these sites the epigenetic remodelling complexes catalyse changes in chromatin biology to influence the expression of oncogenic transcriptional programmes.
This project will involve designing novel TCIP prototypes followed by synthesising and testing these compounds in cell line models of transcription factor-addicted cancer.
Does spontaneous prolonged hypoxia exacerbate brain injury after acute hypoxia-ischemia in near-term fetal sheep?
Project code: MHS039
Supervisor:
Discipline: Biomedical Science
Project
Oxygen deprivation around the time of birth can lead to brain injury in infants, known as hypoxic-ischemic encephalopathy (HIE). Currently, the only approved treatment is therapeutic hypothermia (mild cooling), which significantly improves the rate of death and disability in infants with HIE in high-income countries.
However, a large randomised controlled trial in low-to-middle income countries showed that hypothermia was not effective, and worryingly, hypothermia increased the rate of death in cooled infants. In part, this could be due to babies from low-to-middle income countries having been exposed to prolonged hypoxia-ischemia before birth and/or during labour, as opposed to acute hypoxia-ischemia at the time of birth.
Role
The aim of this project is to compare brain damage as a result of acute hypoxia-ischemia in term equivalent sheep fetuses that have been exposed to spontaneous prolonged hypoxia, versus those with normal oxygenation. This research may help us to better understand how brain injury occurs in fetuses exposed to prolonged hypoxia in utero and how best to treat them.
Skills learned:
– Immunohistochemistry
– Microscopy
– Cell counting
– Image analysis
– Statistical analysis
– Figure preparation for publication
There are also potential Honours/Masters projects available in our lab group.
Investigating the ciliotoxicity of novel antibiofilm compounds
Project code: MHS040
Supervisor:
Discipline: Biomedical Science
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 defense 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.
Role
In this project you will investigate the ciliotoxicity of the most promising 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, tissue culturing and sophisticated microscopy.
This summer studentship can be continued towards Honours, Masters or PhD studies. If interested, please email your CV and academic transcript, and meet us for a chat about the project.
Trained innate immunity induced by traditional and novel vaccines against infectious pathogens
Project code: MHS042
Supervisor:
Discipline: Biomedical Science
Project
Trained innate immunity is a non-specific form of immune memory in innate immune cells in which an initial exposure to a pathogen, commensal, or vaccine “trains” innate immune cells to respond differently to their naïve counterparts on subsequent exposures. This mechanism has been implicated in a variety of pathologies, both as a driver of disease progression and as a mediator of disease recovery. Therefore innate immunological memory can be either beneficial or detrimental.
There is increasing interest in modulating trained immunity to harness the beneficial effects of infection clearance or inflammation control. Additional to immune phenotypic changes, epigenetic and metabolic changes have been observed to occur in innate immune cells following antigenic exposure and are preserved in daughter cells conferring trained immunity.
Role
The summer student, under the supervision of two immunology clinician-scientists, will perform a literature review and critically discuss immunologic, epigenetic and metabolic changes associated with trained immunity as induced by traditional and novel vaccines such as the BCG, MMR and anti-COVID-19 vaccines.
Skills learned
The student will acquire useful research skills including topic analysis, search strategy development, organisation and management of their research, critical appraisal of publications and scientific writing.
Nebulised sodium nitrite as a therapeutic treatment to enhance cerebrovascular function
Project code: MHS046
Supervisor:
Discipline: Biomedical Science
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. However, the optimal dose of nebulised sodium nitrite to increase brain blood flow in humans is currently unknown; a critical first step in translating this strategy into acute stroke management.
Nebulised sodium nitrite can be safely delivered by first responders, providing a novel strategy to rapidly treat stroke patients inside the ambulance. Its potential to extend the therapeutic window for reperfusion could improve stroke outcomes for those living in geographically remote areas like Northland and East Cape. Stroke disproportionally impacts both Maori and Pacific communities, with limited access to stroke care and the worst patient outcomes.
Role
Using vascular and transcranial Doppler sonography to assess brain blood flow, we will identify the optimal dose of nebulised sodium nitrite to improve brain blood flow in patients with hypertension and atrial fibrillation, who are at high risk of stroke. Insights gained from this research will lay the foundation for future clinical trials to examine the use of nebulised sodium nitrite to limit the progression of brain injury in acute stroke.
Colour blind camouflage in octopus
Project code: MHS047
Supervisor:
Discipline: Biomedical Science
Project
An octopus has superb vision and it has exceptionally refined abilities to camouflage on any background – it matches texture and colour of backgrounds in a fraction of a second. However, octopuses have only one type of visual pigment and so should not be able to see colour. Therefore the ability of octopuses to match colour remains a mystery.
Aim
The aim of this project is to reveal the mechanisms that allow octopuses to match colours of background objects that it tries to camouflage in. Octopuses have well developed camera-type eyes that are free from spherical aberrations due to the ideally adjusted graded refractive index of the lens. While octopuses are colour blind, their photoreceptors are polarisation-sensitive, giving octopuses a sophistication of vision that vertebrates generally do not have.
Role
We hypothesize that octopuses extract colour information from polarisation cues. Our preliminary results indicate that certain algae colours can be related to polarisation of light reflected from them. We will perform behavioural experiments to confirm or refute the hypothesis that octopuses use polarisation cues to infer information about colours.
Experiments will be conducted at the Auckland Marine Science Institute (Goat Island).
Oxidative stress in human beta cells as a key signal for the onset of autoimmune type 1 diabetes
Project code: MHS053
Supervisor:
Discipline: Biomedical Science
Project
The onset of human type 1 diabetes (T1D) is often preceded by a prolong clinically silent phase of beta cell dysfunction and appearance of islet cell autoantibodies in serum. In T1D, the adverse immune specificity for beta cells suggests that diabetes-prone subjects may harbour molecular signals of vulnerability in beta cells, which act as conduits for immune destruction of beta cells.
High levels of reactive oxygen species (ROS) in beta cells, such as superoxide anions, hydrogen peroxide and hydroxyl radicals, generated continuously in the respiratory chain, if sustained, result in impaired function and the production of immunogenic beta cell antigens.
Most cells clear reactive oxygen species employing three key enzymes, namely superoxide dismutase (SOD), glutathione peroxidase-1 (GPX-1) and catalase. It remains unclear if human beta cells harbour lower levels of such enzymes than the adjacent endocrine cell-types within the islet.
Role
To study and compare the expression and levels of SOD, GPX-1 and catalase in human pancreatic sections from deceased donors with and without T1D, by multi-label immunohistochemistry.
Laboratory techniques: Pancreatic histology and staining, triple-label immunohistochemistry, bright-field and fluorescence microscopy, imaging, Photoshop, cell quantification by ImageJ (Fiji), preparation of colour plates for publication.
Advancing Small Animal Imaging: Developing and Optimizing Multi-Parametric MRI Protocols with 3T Clinical MRI
Project code: MHS054
Supervisor:
Discipline: Biomedical Science
Project
Magnetic resonance imaging (MRI) is a versatile imaging modality widely employed in biomedical research and clinical diagnosis. The 3T Vida system at the Centre for Advanced MRI is a state-of-the-art 3T MRI equipped with advanced coils for small animals (mice, rats, etc.).
Role
This research project focuses on developing and optimizing multi-parametric MRI protocols to enhance the capabilities of 3T clinical MRI for small animal imaging, including applications such as eye and brain imaging. We will use phantoms and euthanized animals to improve the precision and reliability of imaging data, which is crucial for advancing preclinical studies and translational research in biomedical science.
Skills learned
• Develop a profound understanding of MRI fundamentals.
• Acquire valuable experience in MRI acquisition, optimization, and analysis.
• Cultivate essential laboratory skills required to prepare testing tissues and samples.
Evaluating Targeted MRI for Enhanced Sensitivity and Specificity
Project code: MHS056
Supervisor:
Discipline: Biomedical Science
Project
Role
This summer research project will focus on analyzing images from a novel targeted MRI method to detect and quantify neuroinflammation in the brain. This cutting-edge technique aims to enhance the specificity and sensitivity of MRI in identifying neuroinflammatory processes associated with various neurological conditions such as multiple sclerosis, Alzheimer's disease, and traumatic brain injury.
The project will involve understanding and characterizing the targeted MRI contrast agents and comparing their efficacy with standard clinical MRI in vivo data from a small cohort of patients.
Aim
The overall goal of the research team is to establish a reliable, non-invasive imaging biomarker for neuroinflammation that can improve diagnosis, monitor disease progression, and evaluate the efficacy of therapeutic interventions.
Skills: MATLAB, image processing, data analysis
Understanding the regulation of the glymphatic "brain drain"
Project code: MHS058
Supervisor:
Discipline: Biomedical Science
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). 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 (see Prof Iliff’s Ted Talk on the Glymphatic System: https://www.tedmed.com/talks/show?id=293015).
Role
This summer project will measure glymphatic clearance during activation and suppression of sympathetic activity to the cerebral blood vessels. It is anticipated that this will result in a high impact publication. The successful student will join our friendly and supportive team in the Cardiovascular Autonomic Research Cluster.
Ideal student
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 the opportunity to participate in Manaaki Manawa events throughout the year
Spatial mapping of ocular lens insulin sensitivity - implications for diabetic cataract
Project code: MHS062
Supervisor:
Discipline: Biomedical Science
Project
The normal human lens remains transparent over many decades of life, focussing light on the retina to form a sharp image. Poor blood glucose control due to diabetes is a risk factor for the formation of lens cataract, which disrupts vision and can cause blindness.
The human lens expresses insulin receptors and a putatively insulin-sensitive glucose transporter (GLUT12), yet their specific cellular localisation is unknown. In addition, the responsiveness of GLUT12 to insulin in the lens has not been established.
Role
This project will use tissue culture and immunohistochemistry approaches to spatially localise proteins in the insulin signalling and glucose storage pathways to elucidate the role that GLUT12 plays in lens glucose uptake. This study will contribute to our understanding of normal lens function and potentially contribute to novel therapies to manage diabetic cataract formation.
Skills learned
Tissue culture, tissue sectioning, immunolabelling, fluorescence microscopy, data analysis, report writing
Visualisation of the cochlear vasculature using NZ’s first light sheet microscope!
Project code: MHS063
Supervisor:
Discipline: Biomedical Science
Project
Could any hearing loss arise from underlying vascular pathology? Our peripheral organ for hearing, the cochlea, is a highly vascularised organ. However, we actually know very little about the vascular anatomy and flow in large animals like humans and sheep.
Role
This summer studentship project will explore the use of the light-sheet fluorescent microscope, which has just been acquired by the University of Auckland as the first in NZ, to visualise the vascular anatomy of the sheep cochlea.
We will conduct laboratory-based experiments and analysis to visualise the vasculature in the sheep cochlea using the light sheet fluorescent microscopy technique.
The student will be trained to conduct lab-based work in the Department of Physiology to prepare tissue samples from animal models and to study and use microscopy techniques.
Ideal student
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:
Anatomy of the cochlea, animal cochlear tissue dissection, Immunohistochemistry, light-sheet fluorescent microscopy, image processing, report writing, and literature search.
Visualisation of the cochlea and middle ear using NZ’s first light sheet microscope!
Project code: MHS064
Supervisor:
Discipline: Biomedical Science
Project
Aim
To conduct laboratory-based experiments to visualise the bony niche between the cochlea and the middle ear using the light sheet fluorescent microscopy technique.
About the project
Can we access the inner ear for treatment? Our peripheral organ for hearing, the cochlea, is deeply embedded in the temporal bone of the skull, making its access very difficult. We are interested in developing an intratympanic medical device to access the cochlea through the ear canal. In order to do this, we need to understand the anatomical constraint associated with the intratympanic approach.
Role
This summer studentship project will explore the use of the light-sheet fluorescent microscope, which has just been acquired by the University of Auckland as the first in NZ, to visualise the vascular anatomy of the sheep 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 and use microscopy techniques.
Ideal student
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
Anatomy of the cochlea, animal cochlear tissue dissection, Immunohistochemistry, light-sheet fluorescent microscopy, image processing, report writing, and literature search.
Ferrets as a novel model for investigating the link between traumatic brain injury and neurodegeneration
Project code: MHS065
Supervisor:
Discipline: Biomedical Science
Project
Repetitive mild traumatic brain injuries can lead to a progressive neurodegenerative disorder called chronic traumatic encephalopathy (CTE). To understand how mild traumatic brain injuries can trigger neurodegeneration we need to simulate these injuries in a brain that has a similar structure to that of humans.
Role
This study will investigate markers of neurodegeneration in a ferret model of brain injury. Ferrets are the smallest mammals with a gyrencephalic (folded) brain structure similar to the human brain. We will examine whether markers of neurodegeneration are increased in injured animals compared to controls at a timepoint of six months post-injury. The results will help evaluate whether this ferret model could be used to study the link between head injury and neurodegeneration.
Skills learned
Our collaborators at the University of Adelaide have already performed the experiments and collected the brain tissue for this study. The student selected for this project will learn how to perform multiplexed immunohistochemistry, microscopy and image analysis on tissue sections to evaluate markers of neurodegeneration.
This project has potential to expand to an honours project.
Astrocytes and Tau: Star Players in the Pathogenesis of Chronic Traumatic Encephalopathy
Project code: MHS066
Supervisor:
Discipline: Biomedical Science
Project
Repetitive mild traumatic brain injury in contact sport can lead to a progressive neurodegenerative disorder called chronic traumatic encephalopathy (CTE). CTE pathology involves the accumulation of toxic clumps of tau protein within neurons and astrocytes that surround blood vessels in the cortical sulci. However, it is also common to observe tau tangles within astrocytes at the subpial border of the sulcus in CTE, a pattern of pathology known as age-related tau astrogliopathy (ARTAG).
ARTAG can be seen in neurologically normal individuals and is considered to be related to normal aging, yet the frequent appearance of ARTAG alongside CTE pathology in young individuals potentially challenges this assumption.
Role
In this project we will investigate whether the ARTAG seen in CTE differs from that seen in neurologically normal aged brains by examining different markers of tau pathology. The results will provide new insights into the pathological signature and mechanisms of neurodegeneration in CTE.
Skills learned
The student selected for this project will learn how to perform multiplexed immunohistochemistry, microscopy and image analysis on tissue sections.
This project has potential to expand to an honours project.
Acute and chronic inflammation in uveitis
Project code: MHS067
Supervisor:
Discipline: Biomedical Science
Project
Uveitis is an ocular inflammatory disease that is primarily treated with corticosteroids; however, their long-term use can lead to side effects. Therefore, alternative anti-inflammatory therapies with fewer side effects are actively being sought.
Role
We have recently developed an experimental autoimmune uveitis (EAU) mouse model to assess the efficacy of anti-inflammasome drugs. This project aims to characterise inflammatory marker levels in ocular tissues of EAU mice and correlate these to the disease severity. Particularly, acute and chronic phases of inflammation will be determined to optimise future treatment regimens.
The student will analyse already collected fundus and optical coherence tomography (OCT) images of untreated and treated EAU mice and correlate these with inflammation and inflammasome activity levels seen in confocal images.
Skills learned: ImageJ analysis, disease grading on fundus and OCT images, immunohistochemistry, statistical analysis
Investigating the role of inflammation in perinatal ischemic brain injury?
Project code: MHS072
Supervisor:
Discipline: Biomedical Science
Project
At the time of birth, infants may be exposed to reduced oxygen and blood supply (ischemia), which can lead to death or severe brain damage. Even infants that have mild ischemia have increased risks of brain injury and other neurodevelopmental impairments. However, there are currently no approved treatments for these infants.
We have investigated two promising potential treatment strategies for mild ischemic brain injury in term-equivalent fetal sheep – therapeutic hypothermia and erythropoietin.
Role
During this summer internship, the successful applicant will investigate the role of inflammation in the development of brain injury and whether hypothermia or erythropoietin can reduce this inflammation.
This research will provide valuable insight into how inflammation contributes to brain injury following mild ischemia. Furthermore, this internship will provide critical pre-clinical evidence for potential treatment strategies for brain injury after mild ischemia and will help to inform the development of future clinical trials for the treatment of infants who have suffered mild ischemia around the time of birth.
Skills and techniques learned:
– Immunohistochemistry
– Microscopy
– Data analysis
– Statistical analysis
Please contact us for more information on this summer studentship or to find out more on potential honours and masters projects that we have available.
Regulation of lymphatic vessel growth
Project code: MHS075
Supervisor:
Discipline: Biomedical Science
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.
Role
Almost nothing is known about how lymphatic growth is regulated. To help further our knowledge of this process, we have isolated mutant zebrafish that 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:
– Imaging lymphatic vessel growth in mutant fish
– Mapping genetic mutants to find causative mutations
– Experiments focused on validating candidate mutations i.e. CRISPR/Cas9, gene knockdowns, gene over-expression
Skills learned:
– 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.
Neural control of blood flow through the myocardium: Investigating the intracardiac ganglia (little brains) of the coronary vasculature
Project code: MHS076
Supervisor:
Discipline: Biomedical Science
Project
The intrinsic cardiac nervous system is made up of a large network of cardiac ganglia located in specific regions of the heart. One cardiac ganglionic plexi is next to the main coronary arteries. It is currently unknown how integrating signals within these neurons affects coronary artery blood flow.
Role
This summer, the studentship will investigate the morphology and physiology of intracardiac ganglia associated with the coronary artery. The research will involve the use of nerve tracer labelling and immunohistochemical fluorescence imaging techniques to study the origin of nerve fibres innervating these ganglia and to identify the receptors present in the neurons.
Our laboratory utilizes large animal models, specifically sheep, to study cardiovascular diseases. This project will expose the student to various experimental techniques, such as immunohistochemistry tissue samples, assisting with surgery on anesthetized animals, and collecting data from conscious animals. These activities will provide a deeper understanding of the integrative reflex pathways involved in the neural control of coronary artery blood flow.
Skills learned
– Literature review writing skills
– Immunohistochemistry
– Surgical skills (assisting)
– Analysis of data
– Oral presentation skills
Potential honors and MSc projects are available within our lab group.
Mimicking neovascularization using a 3D human organotypic choroidal sprout model
Project code: MHS084
Supervisor:
Discipline: Biomedical Science
Project
Neovascularization is a critical feature in sight-threatening retinal diseases, including proliferative diabetic retinopathy (PDR) and neovascular age-related macular degeneration (nAMD). The development of effective therapeutics is currently hampered by the lack of clinically relevant tissue models that accurately replicate the process of neovascularization.
Our team has recently characterised and optimised a clinically relevant 3D human organotypic choroidal sprout model. In this model, endothelial tubules sprout from cultured human choroid explant, proving a clinically relevant platform for studying neovascularization. By treating these explants with cobalt chloride to simulate hypoxia, we have successfully replicated the vessel regression that precedes neovascularization.
Role
Further research is required to investigate how endothelial tubules respond to angiogenic cytokines, such as vascular endothelial growth factor, found in eyes affected by PDR and nAMD. The sprouting choroidal explants will be imaged using a light microscope and the total area of growth will be quantified. Culture media will be collected and analysed using different cytokine arrays.
Skills learned: tissue culture, light microscopy, cytokine array analysis, statistical analysis
Ideal student
Part 3 biomedical or optometry student, interested in pursuing a masters degree
Exploring the effect of Aß on retinal endothelial cells
Project code: MHS085
Supervisor:
Discipline: Biomedical Science
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.
Role
This project aims to investigate the effects of aggregated amyloid beta1-42 peptide on human retinal microvascular endothelial cells, and whether 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.
Skills learned
The summer project will involve cell culture, immunohistochemistry, confocal microscopy, and image analysis.
DNA Methylation as a biomarker for preterm pregnancy
Project code: MHS096
Supervisor:
Discipline: Biomedical Science
Project
This project will focus on using genomic DNA sequencing and bioinformatic analyses to understand whether DNA methylation can be used as a biomarker for preterm pregnancy. The project will involve some lab work and a substantial amount of computational work.
Sklls required
Experience with computers (especially command line or programming) or an enthusiasm to learn is required.
You will develop or improve your skills in:
- molecular biology
- DNA sequencing
- bioinformatics and computational biology
The Liggins Institute is dedicated to improving health outcomes across individuals' lifespans, with a focus on the period from conception through early life. Faculty and students work across a wide range of topics, from genomics to brain development to lactation nutrition, and you will have an opportunity to interact with all these researchers.
The immune system strikes back: A hunt for metabolic saboteurs of cancer immunotherapy
Project code: MHS098
Supervisor:
Discipline: Biomedical Science
Project
Immunotherapy can cure cancer but not in all patients yet, as most cancers sabotage the patients’ immunity. Cancers hire saboteur enzymes to produce metabolites that paralyse cancer-killing immune cells and undermine immunotherapies. We aim to hunt these saboteurs down and ultimately make or repurpose medicines to inactivate them and sensitise cancer patients to immunotherapy. We currently focus on discovering saboteurs that make an immunosuppressive tryptophan metabolite called kynurenine.
Role
This research is highly multidisciplinary and spans chemistry, cancer cell and molecular biology and metabolism. It ventures into exciting uncharted territories offering something to any curious mind.
The examples of possible summer projects are below but a project can always be designed to fit your interests. I look forward to talking to anyone keen to explore this fascinating area.
Example projects
1. Developing a 3D-printed tool for discovery of enzymes producing kynurenine in gels using metabolomics and proteomics
2. Testing the function of putative enzyme saboteurs in cancer cells using genome engineering and metabolism measurements using mass spectrometry
3. Exploring the potential of these enzyme saboteurs as cancer biomarkers using nucleic acid sequencing technologies
Probing the transcriptomic signatures underlying Deep Brain Stimulation in Parkinson’s disease
Project code: MHS102
Supervisor:
Discipline: Biomedical Science
Project
Parkinson’s disease (PD) is the second most common neurodegenerative disease after Alzheimer’s disease and is characterized by the degeneration of dopaminergic neurons in the substantia nigra pars compacta. A treatment option for PD is deep brain stimulation (DBS), an invasive procedure involving implantation of electrodes within the basal ganglia to modify brain circuit activity. While DBS is successful for treating tremors and is known to modify brain activity in a structured way, the molecular mechanism underlying its therapeutic benefit is unknown.
Role
In this project, we will investigate gene expression changes in PD brains that have undergone DBS compared to those that haven’t to determine the molecular mechanisms which may underlie the therapeutic benefit of DBS.
Skills learned
The student selected for this project will learn immunohistochemistry, imaging and molecular biology techniques to investigate protein and gene expression from post-mortem human brain tissue.
This project has the potential to expand into an honours project in 2025.
Metabolism in COSMOS
Project code: MHS103
Supervisor:
Discipline: Biomedical Science
Project
Fatty pancreas is the most common disorder of the pancreas. There has been a fundamental shift in our understanding of the pathogenesis of fatty pancreas over the past quinquennium. The overall aim of this project is to provide deeper insights in relation to the metabolic pathways underlying fatty pancreas.
Role
Depending on the learning goals of the successful candidate, the project will involve a quantitative analysis of the existing clinical and laboratory data or a systematic review of published studies. Either way, it is expected that results will be published in an international peer-reviewed journal.
The project is part of a larger research theme of the COSMOS (Clinical and epidemiOlogical inveStigations in Metabolism, nutritiOn, and pancreatitic diseaseS) group. The group offers a vibrant research environment, comprehensive research training, and clinical research experience.
Skills Learned
• Working in a research team environment
• Systematic analysis of metabolism-related biomedical data
• Preparation of a manuscript for publication in an international peer-reviewed journal
Unravel the Dark Side of AML: Fight Leukaemia
Project code: MHS105
Supervisor:
Discipline: Biomedical Science
Project
TET2 and DNMT3A mutations are shadowy figures lurking within the world of Acute Myeloid Leukaemia (AML). These genetic glitches disrupt the delicate dance of DNA methylation, a process crucial for regulating gene expression. In TET2 mutations, this dance goes awry, potentially leading to the transformation of healthy blood cells into their cancerous counterparts.
DNMT3A mutations, on the other hand, cause a similar disruption, throwing a wrench into the machinery that controls the function of genes vital for keeping AML at bay.
Understanding the significance of these mutations is the key to unlocking the secrets of AML progression. By deciphering their role, we can pave the way for targeted therapies that strike a precise blow against the leukaemic cells, while leaving healthy ones unharmed.
Role
This summer, join our research team and be part of the fight against AML! We'll be wielding cutting-edge tools like the tissue-specific CRISPR-CAS9 system, a revolutionary technique that allows us to mimic the effects of TET2 and DNMT3A mutations in zebrafish. This powerful model organism offers a unique window into the inner workings of blood cell development.
We'll dissect how these mutations influence the intricate process of blood cell formation in zebrafish through a combination of next-generation sequencing (which provides a detailed picture of the genetic landscape), qPCR for precise gene expression analysis, live imaging to witness cellular behaviour in real-time, and flow cytometry for categorizing and counting different cell types.
Benefits
Your contribution could be instrumental in developing groundbreaking new treatments for AML patients. This summer internship offers a unique opportunity to gain valuable research experience, collaborate with a dedicated team, and contribute to a project with the potential to improve the lives of countless patients.
Exploring The Impact of ETV6 and WT1 Mutations In AML Progression
Project code: MHS106
Supervisor:
Discipline: Biomedical Science
Project
Dive into the fascinating world of Acute Myeloid Leukemia (AML). Delve into the impact of ETV6 and WT1 mutations, essential players in the intricate landscape of AML progression.
ETV6 mutations disrupt key gene pathways, fuelling the uncontrolled growth of leukemic cells. Meanwhile, WT1 mutations interfere with crucial cellular functions, bolstering AML aggressiveness and resistance to treatment. Our team focuses on unravelling these mechanisms using innovative tools like the tissue-specific CRISPR-CAS9 system in zebrafish models.
Role
Through next-generation sequencing, qPCR, live imaging, and flow cytometry, you'll explore the genetic and cellular intricacies that drive AML evolution. Your research could pave the way for groundbreaking treatments that revolutionize AML therapy.
Finding novel ways to improve heart function in heart failure
Project code: MHS108
Supervisor:
Discipline: Biomedical Science
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). The mechanism of how this works is not fully elucidated yet and will be the aim of this project.
Role
This summer studentship will involve examining tissue oxygenation levels to determine if these can be altered by varying heart rate with respiration. This project will introduce the student to a number of experimental techniques including studies in whole animals and tissue histology from these studies. This will include aseptic surgery techniques (assisting with surgery), conducting experimental protocols in animals and histological analysis of data.
Ideal student
Preference will be given to students who would like to continue on with postgraduate study in the form of an honours or a masters project.
Skills learned
Skills that will be taught and mentored through this studentship include:
– Literature review writing skills
– Collection of physiological data in conscious animals
– Analysis of data
– Oral presentation skills
References
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.
Exploring the link between amplified MRI (aMRI) and high brain pressure
Project code: MHS111
Supervisor:
Discipline: Biomedical Science
Project
Current intracranial pressure (ICP) monitoring requires drilling a hole in the skull to place a pressure sensor. Our team has expertise in brain imaging and integrative large-animal physiology, with an interest in finding methods of measuring ICP, and understanding the physiology of the brain when it is under pressure in applications such as intracranial hypertension, hydrocepalous, Chiari Malformation, and Traumatic Brain Injury.
In our pilot data in humans, we have demonstrated that intracranial hypertension alters cardiac-linked brain motion using our novel method called ‘amplified MRI (aMRI)’. aMRI measures the deformations and movement of the brain tissue and arteries, that occur over the cardiac pulse wave.
Role
Combining aMRI with MRI methods that measure blood flow, the aim of this project is to determine whether cardiac-linked brain motion can provide a diagnostic index of ICP. This project will also help us to help us to understand the relationship between blood pressure, brain tissue motion, blood flow, and ICP.
Skills learned
MATLAB, image processing, data analysis
Building a pioneering child health study with community participation
Project code: MHS112
Supervisor:
Discipline: Biomedical Science
Project
Paediatric imaging studies help understand human anatomy as we grow and develop. They can inform our understanding of normal anatomy and the epidemiology of disease, and help us identify early biomarkers of diseases.
Auckland University and Matai Medical Research Institute are developing an ambitious, long term study to follow up a cohort of children in Tairawhiti district. Advances in MRI technology make this an opportunity to understand the human body in greater detail than before.
This study is being developed with community and academic collaborators. Kaupapa Maori values will be central to the full study.
Role
The research student will assist in designing the full study, building relationships with community stakeholders in the district along with academic collaboration.
Ideal student
We are looking for a student who is interested in child health and Maori health, community participation, and research design. Being a strong communicator will be essential.
The student will be based in Gisborne.
Skills learned
– Understanding research processes
– Working with community stakeholders
– Academic writing
Light mediated killing of fungal biofilm
Project code: MHS113
Supervisor:
Discipline: Biomedical Science
Project
Fungal corneal infections are devastating as they are progressive and require an alternative non-selective therapeutic approach due to increasing antimicrobial resistance. Light-based anti-infective technology has proven effective against many fungal pathogens and inhibits their growth. Although short wavelength light such as UVC kills these pathogens in the in vitro conditions, its efficacy in more stubborn pathogenic environments, like fungal biofilm, is unknown.
Role
Confirming the therapeutic efficacy of novel antimicrobial methods in different in vitro conditions is important for successful clinical translation. The current project encompasses several methods such as microbial viability assessments, confocal microscopy, and advanced image analysis.
Ideal student
This project builds on our ongoing research. A student with a strong interest in translational research, with a focus on infections and diseases, is the right fit for the project.
Skills learned
The student will learn research skills in biomedical science, translational research, medical microbiology, and advanced data interpretation. We expect to publish these data in high-impact journals such as Biofilms (Impact factor = 6.8).
The Gut-Eye-Axis: Unravelling the therapeutic potential
Project code: MHS114
Supervisor:
Discipline: Biomedical Science
Project
The gut microbiota (Probiotics), through the production of metabolites, mucosal mediators, and systemic immune responses, play an important role in the regulation of the immune system. Recent evidence suggests changes in gut microbiota across a range of ophthalmic conditions, suggesting there might be a link between these two distant anatomical sites, which is referred to as the gut-eye axis.
Increasingly, new evidence suggests the therapeutic potential of probiotics in inhibiting harmful pathogenic microorganisms in an infection and accelerating the wound healing process. An understanding of current knowledge in the field and existing gaps will help us formulate novel research questions.
Role
In this summer studentship, the aim is to conduct a critical literature review on probiotics for their potential therapeutic applications.
Skills required
Skills include critical judgement of the existing literature, excellent writing skills, and some knowledge of biomedical research methods.
The review will be published in a high-impact factor journal and will form the base for new research questions in the field.
Understanding aggressive blood cancer using a zebrafish model
Project code: MHS118
Supervisor:
Discipline: Biomedical Science
Project
Acute myeloid leukaemia (AML) is an aggressive type of blood cancer that can be fatal within a few days to weeks if the patient does not receive treatment. The PICALM/MLLT10 (C/A) fusion gene is the result of the chromosomal translocation t(10;11)(p13;q14) and is found in about 1% of all AML patients who have very poor survival.
Mouse models of C/A also show that C/A must be expressed in the correct cellular context to cause leukaemia. Furthermore, patient samples and mouse models of C/A leukaemia show that these leukaemias harbour additional, cooperating mutations.
In our laboratory, we have developed a CA zebrafish AML model (R:CA/MF). To understand the mechanism of malignant transformation in this model, we are expressing CA in different cell types, such as common myeloid progenitor cells, common lymphoid progenitor cells as well as in fully differentiated cells such as neutrophils and T-cells.
Role and skills learned
We are currently seeking an enthusiastic student to join our team and help us with this exciting research. The successful applicant will have the opportunity to learn cutting edge techniques in molecular biology (CRISPR-Cas9 genome editing, qPCR, flow cytometry, Next Generation Sequence sample prep and analysis, in-situ hybridization etc.) and zebrafish husbandry
Lighting up treatments for brain tumours – Investigating near-infrared light enhancement of anticancer drugs for brain tumours
Project code: MHS120
Supervisor:
Discipline: Biomedical Science
Project
Glioblastoma (GBM) is the most common and fatal primary brain tumour in adults, with a median survival time of only 16 months. This dismal outcome is primarily attributed to the limited number of effective tumour-specific anticancer agents that can cross the blood-brain barrier (BBB).
In collaboration with Drs Choi and Jose at ACSRC, we have conjugated known anticancer agents to a class of tumour-targeting and BBB-permeable near-infrared (NIR) dyes called heptamethine cyanine dyes (HMCDs). We have shown that these conjugates elicit potent antitumour effects on both primary human GBM cell lines in vitro, and in mouse models of human GBM. Furthermore, these HMCDs absorb in the NIR range, opening the possibility of enhancing their potency through photo-activation.
Therefore, in collaboration with bioengineers, we have developed an NIR-emitting device that affords high-throughput analyses of the anti-tumour effects in vitro.
Role
Using this system, this studentship aims to test if NIR light can enhance the effectiveness of our conjugates in killing human GBM cells.
Skills learned
The successful applicant will be joining a friendly lab environment at the Centre for Brain Research and working alongside scientists and clinicians to undertake this study. They will learn human cell culture techniques, immunocytochemistry, automated microscopy and high-content image analysis.
Elucidating the effects of radiation therapy on the brain
Project code: MHS121
Supervisor:
Discipline: Biomedical Science
Project
Targeted radiation therapy is vital for treating many primary and metastatic brain tumours. Though effective in treating the tumour, it inevitably causes damage to the surrounding brain tissue, resulting in cognitive decline and reduced quality of life. Radiation-induced gross injuries to the brain are well-known; however, there is little information about the subtle effects of radiation on the physiological function of discrete brain cell populations.
Role
Previous studies in rodent brains have uncovered some alterations in glutamatergic synaptic activity and neuroinflammatory responsivity. This study aims to further these investigations by elucidating changes in cellular function, homeostasis, and inflammation, at a much more intricate single-cell level.
We will employ multiplex immunohistochemistry and single-cell image analysis to elucidate cellular changes in discrete brain cell populations in rodent brains exposed to various therapeutic single doses of gamma-irradiation. Specifically, neurons, astrocytes, oligodendrocytes, microglia, pericytes, and endothelial cells will be co-labelled with DNA damage and neuroinflammatory markers to garner a comprehensive picture of the cellular microenvironment post-irradiation.
Together, this project aims to investigate the cellular changes that lead to radiation-induced cognitive decline and help find therapeutic targets that could potentially alleviate these neurological side effects of radiation therapy.
Unlocking Personalized Treatments for Parkinson’s: Targeting Alpha-Synuclein Strains and Brain Cell Variability
Project code: MHS124
Supervisor:
Discipline: Biomedical Science
Project
Parkinson’s disease (PD) is the fastest-growing chronic neurological disorder, affecting 10 million people globally. Existing treatments only alleviate symptoms and do not halt disease progression. The formation of alpha-synuclein aggregates is known to play a critical role in toxicity and progressive neurodegeneration. However, this does not fully explain the variability in affected cell types and the diverse symptoms experienced by PD patients.
Recent discoveries have identified distinct structural and phenotypic differences in fibrillar alpha-synuclein aggregates, leading to the hypothesis that various 3D conformations or ‘strains’ of alpha-synuclein may contribute to the heterogeneity of PD.
We propose that the variability in PD can be categorised based on these alpha-synuclein strains, and that effective treatment must be tailored to each specific strain. Through RNA sequencing, novel vital genes and proteins associated with these specific strains have been identified. Targeting these genes and proteins could pave the way for new therapeutics that address the underlying mechanisms of PD.
Role
This project aims to validate the expression of these newly identified targets in human brain sections from both PD patients and healthy individuals. You will investigate cell-type specificity, protein localisation in relation to alpha-synuclein aggregates, cellular compartments, and regional variability throughout the brain.
Targeting Strain-Specific Alpha-Synuclein Aggregates in Parkinson’s Disease and Multiple System Atrophy
Project code: MHS125
Supervisor:
Discipline: Biomedical Science
Project
Parkinson’s disease (PD) and Multiple System Atrophy (MSA) are neurological disorders affecting 10 million people worldwide, with no current curative therapies due to their complexity and symptom variability. Central to these conditions is the formation of toxic alpha-synuclein (a-syn) protein clumps. Although the building blocks of these aggregates are the same, their 3D structures can vary, creating unique a-syn 'strains' responsible for the observed heterogeneity in patients. These strains remain stable and act as templates for further aggregation.
Role
Our project aims to identify therapeutic targets that reduce these a-syn clumps in the brain, hypothesising that treatment must be strain-specific. We have identified prominent gene changes by exposing brain cells to specific a-syn strains.
This summer, you will validate these gene changes in human brain tissue from PD and MSA cases, examining cell-type specificity, protein localisation, and cellular compartments. Techniques will include live cell imaging and AAV transduction.
By validating these targets, we will move towards testing whether altering gene expression can reduce strain-specific a-syn clumps, potentially reducing the burden of these aggregates in the brain and paving the way for novel, targeted treatments for PD and MSA.
An investigation into brainstem injury after hypoxia-ischemia
Project code: MHS126
Supervisor:
Discipline: Biomedical Science
Project
From the beginning of a preterm infant’s life, brain injury caused by reduced oxygen and blood flow to the brain (hypoxia-ischemia) before and around birth can cause life-long disability. This ranges from mild neurodevelopmental disorders to severe motor and cognitive disability, which can have a profound impact on a survivor’s quality of life.
There are no treatment strategies as we still need a greater understanding of how brain injury evolves over time.
Our group has a well-established animal model of hypoxic-ischemic brain injury, and we are now investigating brainstem injury. Clinically, very little is understood about the pathology of brainstem injury: only that it is associated with an elevated risk of apnoea of prematurity, congenital central hypoventilation syndrome, and sudden infant death syndrome.
Role
The aim of this preliminary study is to improve our understanding around the pathology of brainstem injury by identifying potentially vulnerable autonomic centres and predicting the onset and progression of injury.
The successful applicant will participate in the assessment of fixed brain sections using immunohistochemical staining and microscopy, data analysis, and basic statistical methods. There is also potential to investigate associations between brainstem injury and impaired lung function and development.
The cerebral effects of hypercapnia measured with EEG
Project code: MHS128
Supervisor:
Discipline: Biomedical Science
Project
Increased concentration of carbon dioxide is known to cause cognitive impairment and, eventually, loss of consciousness. In anaesthesia EEG monitors are used to measure the level of consciousness. Previously, two novel quantitative EEG analysis algorithms have been developed that were sensitive to other narcotic agents.
Objective
This study aims to use the two analysis algorithms to test the hypothesis of the sensitivity of these algorithms for carbon dioxide as a possible method of early detection of hypercapnia.
Methods
EEG recordings will be analysed in Matlab (computational software) using previously developed analysis algorithms.
Research impact
This research will help to increase the understanding of the cerebral effects of carbon dioxide and the effect this has on the EEG recorded.
Skills learned
• Teamwork and research coordination skills
• Helping 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