Biomedical Science

Postoperative infection is a serious problem in New Zealand, and internationally with considerable human and financial costs. To date, most efforts to reduce postoperative infection have focused on surgical aspects of care and on antibiotic prophylaxis, but recent research shows that anaesthesia providers may also have an impact on infection transmission [1].

We have collected observational data on key anaesthetic practices from orthopaedic theatres using a behaviourally anchored rating (BAR) tool that has been specifically developed for a large, multi-site quality improvement project (The ABC Study). This study is confined to orthopaedic theatres.

You will observe these key anaesthetic practices in non-orthopaedic operating theatres and compare the data from this with data from orthopaedic cases to ascertain if the practices have spread beyond the boundaries of the ABC Study. You will be trained in the use of the BAR tool and observe anaesthesia teams in selected operating theatres at Auckland Hospital. This project would suit a student from the health science disciplines.

Skills learnt

• Literature review and critical appraisal
  
• Data collection including observing surgical cases in operating theatres
• Statistical analysis
• Oral presentation skills
• Preparation of a report/publication – medical writing

Please contact Dr Gargiulo after 8th July.

[1] GARGIULO D, MITCHELL SJ, SHERIDAN J, SHORT T, SWIFT S, TORRIE J, WEBSTER CS, MERRY AF. Microbiological contamination of drugs administered for anesthesia in the operating room: a prospective, open, microbiological audit. Anesthesiology 124, 785-94, 2016.

In this project, the student will work with clinician scientists in the clinical physiology laboratory and assess results of autonomic studies in pregnancy. There will also be an opportunity to assess women's views about taking part in the protocols needed to assess responses to orthostatic manoeuvres ( effects of standing up and lying down) in pregnancy.

The student will analyse a short questionnaire that women have completed about the physiology studies they have experienced.
Skills required are interests in applied physiology including in pregnancy, working with data and simple statistics.

The potential impact of this project will be to assist in the design of an easy clinically useful test that can be used to assess women at risk of supine hypotension which affects 8-10% of women by late pregnancy.

The student will work with a clinical physiologist who is now completing a PhD in gestational changes in cardiovascular autonomic responses in pregnancy and who will provide all the necessary data and who also will provide the student with opportunities to work in a clinical physiology laboratory.

The project could begin before the year's end as the necessary data are available now. 

Lens cataract is the leading cause of blindness and is estimated to reach 30 million as the world’s population ages. Faced with a looming cataract epidemic, research has focused on developing anti-cataract therapies to delay cataract and reduce the need for surgery. Since cataract is associated with oxidative damage, the use of antioxidant supplements has been advocated as a therapeutic approach to slow cataract progression. However, studies into their efficacy are mixed and in some cases, antioxidant supplementation has been shown to have pathological effects. The reason for this may be explained by accumulating evidence that suggests that rather than being harmful, physiological levels of reactive oxygen species (ROS) may in fact be beneficial, acting as signalling molecules important in maintaining normal cellular processes.

The overall aim of this research project is to better understand the role of physiological ROS in the lens with a focus on identifying ROS-mediated signalling pathways in the lens required for normal lens function and transparency.

Techniques acquired during this studentship include lens dissection, tissue culture, immunohistochemistry and microscopy.

Heart rate fluctuates with breathing. This variability is prominent at birth and exaggerated in elite athletes. As we age, this variability is reduced and is lost with the development of heart disease. Recent studies suggest that the changes in intra-thoracic pressures during the act of respiration have differential effects on the left and right sides of the heart. This variability in cardiac output has serious implications for how the next generation of pacemakers are designed. We will utilise a large animal model to explore changes in left and right heart dynamics during the act of breathing. The consequences of this for perfusion of different organs will be explored.

This project will introduce the student to a number of experimental techniques in conscious animals. Preference will be given to students who WANT to continue on with an Honours or a Masters project.

Skills taught and mentored during this studentship include:

• Literature review writing skills
• Surgical skills (assisting)
• Collection of physiological data in conscious animals
• Analysis of data
• Oral presentation skills

The musculoskeletal architectural parameters of infants under one year old has never been investigated using 3D ultrasound. In this project we will be using computer based ultrasound with motion capture ultrasound to investigate the fibre bundle length, pension angle and volume of the muscle.

This project needs a thorough literature search, understanding the basic of ultrasound to be able to analyse the images and statically analysing the result. It begins from the first of November for 10 weeks. 

Aside from the established role for platelets in regulating hemostasis and thrombosis, recent research has revealed a discrete role for platelets in the separation of the blood and lymphatic vascular systems. Platelets are activated by interaction with lymphatic endothelial cells at the lymphovenous junction, the site in the body where the lymphatic system drains into the blood vascular system, resulting in a platelet plug that, with the lymphovenous valve, prevents blood from entering the lymphatic circulation. This process, known as "lymphovenous hemostasis," is shown in animals and never been investigated in human.

In this project, we will histologically investigate 20 lymphovenous junction (LVJ) harvested from cadavers donated to the University of Auckland.
This project includes a thorough literature search, harvesting 20 LVJ, investigating the presence of platelets at the LVJ using histology.

Please contact Dr Mirjalili for the details of this project.

Retinal diseases are currently treated by frequent injections of the drug into the eye ball, an invasive procedure that has to be performed by a specialist. Self-administration of these drugs as topical eye drops would therefore be of great advantage. While topically applied drugs are generally unable to reach the retina in sufficiently high concentrations, recent research utilizing novel drug delivery systems has shown success in transporting molecules across the ocular barriers and to the back of the eye. However, little is known about how drugs distribute from the front to the back of the eye.

Matrix-assisted laser desorption/ionization (MALDI) imaging is becoming an important technique to determine drug distribution after dosing in preclinical species. And while interest in MALDI in the ophthalmology field is growing, only a few studies have been published with regards to drug distribution in the eye. This project aims to combine an ex vivo porcine whole eye penetration model with whole eye ball sectioning and MALDI imaging to map drug distribution after topical eye drop administration.

The ocular lens plays a crucial role in focussing light onto the retina to facilitate vision. Cataract, the opacification of the lens, is the leading cause of blindness worldwide, with leading risk factors diabetes and aging leading to specific cataract phenotypes. These lens region-specific optical changes are the result of alterations to the lens proteins, lipids, and metabolites associated with cataract formation. Changes to these lens biomolecules may also have implications for the health of other ocular tissues.

This project aims to identify specific disease-related molecular changes that could be targeted for future therapeutic interventions by applying advanced biomedical imaging tools to characterise the molecular changes underlying cataract formation.

Skills

• lens dissection
• tissue sectioning
• MALDI imaging mass spectrometry
• optical microscopy
• data analysis 

Obesity is almost always associated with fatty liver disease that can progress to liver failure. Our preliminary data has identified novel genes that might play a role in fatty liver disease and we plan to treat mice with a drug to mimic the action of this gene to determine whether this drug can be used to treat fatty liver disease.

This project will be focused around using cell culture and/or mouse models to understand the molecular mechanisms that underpin the development of non-alcoholic fatty liver disease and its translation to non-alcoholic steatohepatitis.   

Type 2 diabetes (T2D) is one of the largest growing health issues within New Zealand, and is closely linked with the development and progression of cardiovascular diseases, including cardiac dysfunction, arrhythmias and heart failure. Research using animal models of diabetes suggest that the development of diabetic heart disease is progressive, resulting in subcellular changes in the cardiomyocytes that impair cardiac function. Recent animal studies have shown that exchange proteins activated by cAMP (known as “Epac”) induce alterations in intracellular Ca2+ regulation when activated in many cell types, including cardiomyocytes. Cyclical changes in intracellular Ca2+ are key in controlling cardiomyocyte contraction and relaxation, which enables the heart to function as a pump. Previously we have shown that Epac activation of healthy cardiomyocytes causes Ca2+ leak from the sarcoplasmic reticulum (SR), which is the intracellular Ca2+ store. This in turn means less Ca2+ is available for excitation-contraction coupling.

The aim of this summer studentship project is to quantify the relative abundance and distribution of Epac proteins in human atrial tissue obtained from consenting diabetic and non-diabetic patients. Fixed tissue samples will be sectioned and antibody labelled with specific Epac antibodies and key excitation-contraction coupling proteins. Images will be taken using confocal microscopy and quantification carried out.

This project would ideally suit a student with a strong background in cardiac muscle physiology who are considering a research career.

Skills that will be taught and supervised include:

• Cryosectioning
• Immunolabelling
• Confocal microscopy
• Data collection and statistical analysis
• Literature review and scientific report writing
• Presentation of results

Our team is currently investigating why female stem cells from the human eye consistently outperform their male counterparts in proliferation, differentiation and migration - three important parameters in tissue homeostasis. Is this the reason that women live longer than men?

The project will use stem cell culture, confocal and time-lapse microscopy coupled with qPCR to determine the mechanisms that define why female stem cells are stronger for longer.

The Insulin-like growth factors are key regulators of both growth and metabolism. IGF-II is essential for normal fetal growth and although it is known to be involved in cancer progression, it's role in adult health is poorly understood. It is becoming clear that most tissues have some low level of IGF-II expression that is key for maintenance, turnover and growth (e.g. increase in islet beta cell mass in times of increased insulin requirement). IGF-II is also capable of metabolic (insulin-like) activity and to what extent and how IGF-II is involved in normal metabolic regulation or dysregulation is unclear.

An interesting element of IGF-II biology is the presence of binding proteins that hold on to and prevent IGF activity. Adults have a large pool of circulating IGF-II in concentrations which could cause dangerous hypoglycemia, however this IGF-II is all bound up to specialised binding proteins which prevent activity. Our lab is interested in all these poorly understood elements of IGF-II biology and how they relate to metabolic disease. One of the key things we'd like to understand is the tissue specific expression of IGF binding proteins and how these may be altered in insulin resistance.

We have developed cell-based models of insulin resistance in muscle and fat cells and we want to characterise the binding proteins in these models. There is a scarcity of data in the literature on tissue-specific expression of these proteins in insulin resistance and this data will tie in nicely to work we already have enabling the student's work to contribute to a high quality publication.

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by a lack of social interaction and communication, and excessive repetitive behaviours, affecting approximately 1% of New Zealanders. Such ASD-related behavioural deficits are thought to be underlied, in part, by functional disruption at synapses, sites of neuron-to-neuron contact and communication, and thus, synapses are considered as major targets of potential therapeutic intervention to treat people with ASD.

The Synaptic Function Group led by A/P Johanna M. Montgomery has recently shown that providing animal models of ASD with diets enriched in zinc, a prevalent metal in the brain known to modulate synapse structure and function, can reverse ASD behaviours. However, the molecular and cellular mechanisms underlying this high zinc diet-induced rescue of behavioural deficits observed in the animal models of ASD are yet to be elucidated.

The project will involve immunohistochemistry, confocal microscopy, and image analysis techniques to identify the potential zinc-dependent changes in the synapse structures of ASD mouse brains.

Our research lab is interested in developing and characterising connexin43-based treatments for chronic eye diseases. Currently, our lab develops and uses in vitro and in vivo models to evaluate the efficacy and mechanism of action of connexin43 hemichannel targeting molecules for the treatment of diabetic retinopathy and age-related macular degeneration. The project proposed here will involve the development of a novel human retinal tissue explant model of these diseases in which to evaluate the effectiveness of connexin43 channel blockers.

The kidneys are crucial organs for waste excretion from the body and maintaining the fluid and electrolyte balance of the blood. Damage to the kidneys caused by diabetes and hypertension, acute kidney injury by toxins, sepsis or ischemia as well as congenital renal malformations and renal cancers can progress to chronic kidney disease, a major global health concern.

In recent years, organoids generated from human pluripotent stem cells have revolutionised how organ development and disease are studied. To overcome the urgent need for effective therapies for kidney disease, our lab has established a method to grow kidney organoids from human induced pluripotent stem cells (Przepiorski et al., Stem Cell Reports, 2018). Organoid development resembles nephrogenesis as it occurs in the human fetus and results in multiple kidney tissue types with high degree of maturation. Approaches currently undertaken in our lab use these kidney organoids to recapitulate different types of kidney disease (including acute kidney injury, kidney fibrosis, renal cancer, congenital kidney malformations), with the aim of improving our understanding of the molecular mechanisms underlying these diseases and ultimately, developing new therapeutic options.

The summer student will be focusing on one of these projects. The following techniques will be used:

• Histology (paraffin embedding, sectioning, HE- and trichrome staining)
• Fluorescence immunohistochemistry and imaging (light and confocal microscopy)
• RNA isolation and qPCR
• Data analysis and presentation

Please send a CV and academic transcript if interested.

Nephropathic cystinosis is a rare inherited lysosomal storage disease caused by defective transport of the amino acid cystine from lysosomes into the cytosol due to mutations in the cystine transporter gene CYSTINOSIN (CTNS). Loss of CTNS causes cystine to accumulate in lysosomes where it is poorly soluble and crystallises, leading to widespread tissue and organ damage. Kidney tubule function is compromised resulting in excess urinary excretion of essential nutrients and low-molecular weight proteins (known as Fanconi syndrome). There is no cure for this disease.

We have discovered a new combination therapy that has shown great promise in our cell line model. Pre-clinical trials of new treatments for this disease are difficult as there are limited animal models that fully recapitulate the human phenotype. In an effort to develop a better model, we have recently generated the a rat model of cystinosis. Using this model we will test our new combination therapy and determine the therapeutic benefits.

The aim of the summer project will be to quantitate, and process data collected from biological samples of the cystinotic rat. The student will perform Blood Urea Nitrogen and creatinine measurements on plasma collected from rodents to determine the function of the kidney with and without treatments. 

Birdsongs learn their song in a way which resembles how humans learn to speak. They memorize the songs of a tutor (usually their father) and then listen to their own song until they produce a mature song that resembles that of the tutor. Auditory processing, then, is important in a birds ability to learn to sing a good song. In social birds, and in nature, the auditory system also needs to distinguish between songs of different conspecifics and songs from heterospecific species.

The auditory nuclei of the forebrain of songbirds have been shown to help process conspecific developmental signals. What we do not know is where along the auditory pathway this ability first emerges. In the bird brainstem, auditory nuclei have been studied primarily in the context of sound localization. But zebra finches are poor at sound localizing and they also show adaptations in their connections that are inconsistent with them being involved in sound localization. Is it possible then that these nuceli have adapted their circuit to support the learning and maintenance of song production?

What we are looking for in a successful applicant

The student should have a basic background in biology and neuroscience.

Objective

This project aims at describing the development of the connections of the auditory system in zebra finches, to identify the developmental steps that lead to the reorganization of connections between the auditory brainstem nuclei.

This project will allow the student to learn

• Basic processes that lead to the development of the nervous system
• Histological techniques
• Image analysis of histological sections
• Immunohistochemistry
• Labelling of axonal circuits

New Caledonian crows are well known for their ability to manufacture and use tools that they then to obtain food. New behaviours can only evolve in parallel with adaptations in the nervoous sytem. What these neural adaptations are in the context of tool manufacture in crows remain unknown. This project aims to identify what neural adaptations may have facilitated the evolution of tool manufacture and use in New Caledonian crows and to determine which area/s of the brain are the substrates for this behaviour.

Skills

The project will involve primarily neuroanatomical techniques (histology, immunocytochemistry, 3D brain reconstructions), but the data will be integrated with behavioural data already obtained by Drs Gray and Hunt.

We know where a sound comes from by comparing the timing of arrival of sound to the two ears. The sensory information that is processed through the cochlea provides no information about where a sound is coming from, so this information needs to be computed by neurons in the brainstem. Neurons in the brainstem measure the delays associated with the transmission of the action potentials from the ears to the brainstem and translate these interaural time differences into information about space.

By measuring these transmission delays experimentally, we can begin to build models around how sound localisation is made possible by the auditory brainstem circuits.

This project involves learning about the anatomy and physiology of the auditory system, the computational processes that enable sound localisation, the development of software to analyse neural data, and histological tools that answer some questions about the specialisations of neural circuits.

Brain-machine interfaces are used to extract the neural code associated with a behaviour, and use that code to drive a robotic device. In the context of human health, it allows people with motor disabilities to have their brains ‘talk’ directly to a device, such as a prosthetic arm.

We are currently trying to exploit this technology to study how auditory and somatosensory information contribute to the production of speech. We are using a songbird as an animal model because the neural substrates and the process of learning song are similar to those of humans. To separate the processes that are involved in the ‘intention’ to sing from the act of singing itself, we are training birds to learn how to ‘sing’ (through a brain-machine interface) using an audio speaker rather than through their vocal apparatus.

The project involves understanding the models of auditory-vocal learning and vocal production, understanding how vocal motor commands are coded in ‘motor cortex’, how these can be analysed through machine learning algorithms, and animal behaviour analysis.

To aid novice snorkelers some manufactures have developed a full face snorkel mask. This full face snorkel mask is specifically advertised for children and novice swimmers. In the last couple of years concerns have been raised about their safety. Seemingly healthy and capable snorkelers have been found dead in the water while wearing such a full face mask. It has been suggested that at least certain masks will allow rebreathing of the exhaled gas, leading to high carbon dioxide levels. There is no publicly available data to on the safety of such masks.

This project will measure the breathing contents while participants are breathing from a full face snorkel mask. Measurements will be performed while participants are sedentary and while exercising. Healthy adults and children will be invited to participate in this research. The outcomes of this research will potentially have a huge impact in the snorkeling/diving community. The measurements will be conducted in the Exercise Science building at the Newmarket campus. This project would suit a student from the health including exercise science disciplines.

Recently, there have been some animal studies showing bidirectional communication between the gut microbiome and brain. Gut microbes actively secrete neuroactive substances and some human studies have shown altered gut microbial diversity in patients with major depressive disorder. Gut microbes affect the brain through the Vagus nerves, enteric hormone systems and also by creating a leaky gut and activating the inflammatory pathways in our body. We know that decreased microbial diversity is associated with Parkinson’s disease, inflammatory bowel diseases as well.

We also know that gut microbes can be altered by age, food habits, exercise, psychological stress apart from the above disease conditions. Gut microbes can also be altered by antibiotic treatment. Probiotics have been used recently to manage the above iatrogenic damage to the gut microbiome and it has been found to be beneficial in reducing symptoms of Major Depressive Disorder as well.

A systematic review of the gut microbiome in depression will help improve the understanding of this important and emerging field of medicine. 

Aims

Melanoma is an aggressive cancer known to have high propensity to metastasize to the brain. This however, requires disruption of the structural integrity of the blood-brain barrier (BBB) thought to occur through interactions of adhesion molecules expressed on the brain endothelial cells and the melanoma cells. An increasing number of molecules have been shown to participate, to some extent, in melanoma mediated disruption of and migration through the BBB. The importance of these molecules in literature varies across different melanoma and endothelial cell lines suggesting the occurrence of variability in means of metastases, within the same cancer type.

The aim of this study is to identify key molecules of interest that facilitate melanoma mediated disruption of the brain endothelium and subsequently allow their traversal into the brain parenchyma. If we determine what a range of key molecules are, we can block them to investigate therapeutic benefit toward melanoma migration into the brain, for a variety of differing melanoma types.

Potential skills to be gained during the summer research programme:

• Cell Culture
  
• Electric Cell-substrate Impedance Sensing – barrier studies
• Immunocytochemistry
• Flow-cytometry
• Live-cell imaging
• Live-cell functional assay
• Scientific report writing

Glioblastoma Multiforme (GBM) is a highly aggressive primary brain tumour that circumvents current radio-, chemo- and immune-therapies. FDA approved immunotherapies such as ipilimumab and nivolumab have failed to induce durable responses in GBM patients, likely in part due to a broad range of immune-suppressive mechanisms utilised by GBM to evade immune elimination. Therefore, the need to further understand the mechanisms involved in promoting immune evasion is necessary.

A recent paradigm shift in GBM research is the discovery of populations of GBM specific cancer stem cells within primary tumours. Studies have shown that these populations are particularly resistant to radio- and chemo-therapies, likely serving to re-establish tumour bulk following treatment. However, their role in promoting immune evasion is less well understood. This project aims to characterise the expression of molecules known as inhibitory checkpoint ligands on GBM cell lines and understand the role of increased stem-like properties on the expression of these molecules.

Project will involve working with human cells, analysis by flow cytometry, and immunocytochemistry. The research team is based in the Centre for Brain Research at Grafton.  

The gut microbiome plays an important role in early immune development and starts developing towards mature, adult composition immediately after birth. Orally administered dextrose gel is a simple and effective treatment for low blood sugar levels in babies. Clinicians and parents are often concerned about the effects this treatment has on the gut microbiome, which are not known nor have been studied.

The hPOD trial is currently recruiting babies at risk of low blood sugars to determine whether giving preventative dextrose gel can reduce low blood sugar levels and admission to intensive care. To assess treatment’s effect on the gut microbiome, we recruited 180 babies, whose early gut microbiomes will be profiled by DNA sequencing.

This summer project aims to extract DNA from the collected stool samples for subsequent DNA analysis. This is a great opportunity to learn about modern methods for microbial community analysis, and to get started your journey in learning about the human gut microbiome, our fellow travelers. There is a possibility to continue working in the study after the summer period.

Atropine eye drops are currently the most effective method for inhibiting progression of myopia (short-sight), but the site(s) of atropine’s anti-myopia action are controversial. There is some evidence that atropine may act to affect neuronal activity within the retina. Recently, it has been postulated that the selective stimulation of the ON- and OFF-pathways in the retina can modify axial elongation of the eye and thickness of the choroid, both of which are associated with the rate of myopia progression.

The aim of this project is to investigate the short-term effect of atropine eye drops on the ON-OFF electrical responses in the human retina. A demonstration that atropine selectively influences retinal responses related to the ON- and OFF-pathways would lend further weight to a retinal site of atropine’s anti-myopia action and provide additional insights into our investigation of the mechanisms underlying atropine’s efficacy in controlling myopia.

Skills that will be acquired during the project

• Recruiting research participants and conducting ERG experiments
• Procedures for recording and analyzing the ERG responses in human subjects
• Analysis of the relevant literature

Talazoparib is the most potent PARP inhibitor currently in clinical use. PARP inhibitors are known to act via a combination of catalytic inhibition and trapping of PARP-DNA complexes; the relative contributions of these mechanisms are still being explored. It has been demonstrated that although talazoparib has similar IC50 values in isolated enzyme assays to other PARP inhibitors, it is significantly more potent in cell culture (100x vs. olaparib). This difference has been attributed to the ability of talazoparib to trap PARP-DNA complexes more efficiently than other PARP inhibitors. Recent research indicates that the trapping mechanism is a double edged blade, along with the increase in potency comes an increase in toxicity. A previous summer student has established a route to potential hypoxia-activated prodrugs of talazoparib and this project will continue exploration of this synthesis.

Students interested in this medicinal chemistry project should have at least second year organic chemistry knowledge (Chem230). The Auckland Cancer Society Research Centre provides a multidisciplinary and collaborative environment. Opportunities exist for the right candidate to pursue further studies in cancer drug discovery.

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.

In our pilot data acquired on our large-animal (sheep) experimental model, 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. 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 -- and potentially open up other clinical applications in diagnosing other disorders that can alter ICP such as hydrocephalous, Chiari Malformation, and Traumatic Brain Injury.

Skills

• MATLAB
• image processing
• data analysis
• physiology
• large animal models

Hydrogels are commonly used depot formulations for drug delivery. Recently, it has been observed that ultrasound can alter drug release from these systems. When combining the two for treatment, it will be possible to administer a hydrogel as a long term depot system and use ultrasound to specifically release drug from the depot when needed. While the ability to do this has been confirmed, the mechanism by which ultrasound instigates drug release from hydrogels is still unclear and the technique has not yet been optimised. As such it remains important to assess the behaviour of different types of hydrogels under different ultrasonic conditions.

In this project, the viscoelastic and drug release properties of gels will be analysed before and after application of different ultrasonic protocols.

Skills learned

• gel formulation
• oscillatory rheology
• drug diffusion studies
• UV-Vis spectrophotometry

CSF-1, also known as macrophage (M)-CSF, is a hemopoietic growth factor for the mononuclear phagocyte lineage and the primary regulator of macrophage differentiation, proliferation and survival. Expression levels of CSF-1 and CSF-1R correlate with tumour cell invasiveness and adverse clinical prognosis in breast, ovarian and prostate cancers.

Macrophages switch between two main phenotypes M1 (pro-inflammatory and immunostimulatory) and M2 (anti-inflammatory and immunosuppressive). CSF-1R signalling pathway is known to promote recruitment of M2 macrophages to the tumour microenvironment. CSF-1 and CSF-1R promote tumour-associated macrophages (TAMs) which in turn promote tumour progression and metastasis.

CSF-1 has direct effects on tumour growth release of tumour-derived inflammatory mediators. CSF-1R inhibition targets tumour stroma tumour itself, preventing tumour growth and metastasis. Designing drugs that can inhibit CSF-1R would reprogram macrophages from M2 to M1 phenotype. Our Research group has been developing novel CSF-1R inhibitors as anticancer agents.

In this project, you will be involved in the chemical synthesis of inhibitors and their initial

• pharmacokinetic evaluation (mouse/human plasma stability, protein binding and in vitro liver microsome stability)
• plasma and tissue pharmacokinetics in mice in vivo
  

Skills you will gain

Organic/Medicinal chemistry in drug development: compound synthesis, purification (chromatography techniques) and structure identification (nuclear magnetic resonance (NMR) spectroscopy, high performance liquid chromatography/mass spectrometry) and the use of scientific data bases (Scifinder, Agilent MassHunter) and pharmacokinetic software (Phoenix WinNonlin).

Skilled gain in CHEM230 second year course would be an advantage.

Alzheimer's disease (AD). AD is characterized by progressive loss of neurons, memory and other cognitive functions. Currently, there are still no effective treatments to prevent, delay or reverse AD. A feature of the pathogenesis of AD is the increased concentration of neurotoxic soluble oligomers of beta amyloid peptides. Optogenetics is the combination of genetic and optical methods. It uses light-activated ion channels (opsins) for temporal control of neuronal excitability limited to specific selected cell-types mediated by viral vectors and light stimulation that is delivered at a specific brain region; and predicted to be the next generation of deep brain stimulation technology.

The aim of this project is to design an optogenetic stimulation approach to ameliorate beta amyloid-induced changes in neuronal function and behavior in an in vivo Alzheimer's disease mouse model.

We offer a stimulating and collaborative research environment. The successful candidate will join a lively community of students at the Centre for Brain Research. The ideal candidate is ambitious and highly motivated for pursuing a career in neuroscience.

Skills taught

• animal handling
• stereotactic brain surgery
• mouse behavioural testing
• neural tissue collection, fixation
• combination of molecular, anatomical and imaging techniques
• data collection, analysis and presentation

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease which presents with the loss of voluntary movement resulting in dance-like movements, behavioural and psychiatric symptoms along with cognitive decline. The cingulate cortex plays a vital role in learning, memory and emotion processing. Previous research in our laboratory suggests that the cingulate cortex is affected in HD, and mood symptoms in HD cases are linked with major cell loss in this brain region.

The aim of this project is to investigate whether the degree of the neuronal loss in the cingulate cortex of human HD cases correlates with other pathological hallmarks of the disease using immunohistochemistry on tissue sections of HD cases and controls.

We offer a stimulating and collaborative research environment. The successful candidate will join a lively community of students at the Centre for Brain Research. The ideal candidate is ambitious and highly motivated for pursuing a career in neuroscience.

Skills taught

• human post-mortem tissue processing
• immunohistochemistry
• light and confocal microscopy
• data collection, analysis and presentation

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease. Previous studies have reported significant neuroinflammatory changes in HD. Whether these changes are neuroprotective or are further destructive is still unclear. Similarly, the impact of neuroinflammation in controlling cellular and molecular pathways leading to cell death is not well understood. The cingulate cortex plays a vital role in learning, memory and emotion processing. Previous research in our laboratory suggests that the cingulate cortex is affected in HD.

The aim of this project is to investigate whether there is significant neuroinflammation in the cingulate cortex of human HD cases using immunohistochemistry on tissue sections of HD cases and controls.

We offer a stimulating and collaborative research environment. The successful candidate will join a lively community of students at the Centre for Brain Research. The ideal candidate is ambitious and highly motivated for pursuing a career in neuroscience.

Skills taught

• human post-mortem tissue processing
• immunohistochemistry
• light and confocal microscopy
• data collection, analysis and presentation

The musculoskeletal architectural parameters of infants under one year old has never been investigated using MRI. In this project we will be segmenting images captured by MRI to investigate the volume of the left and right gastrocnemius muscles in 6 months old infants.

This project needs a thorough literature search, understanding the basic of cross-sectional imaging to be able to analyse the images and statically analysing the result. It begins from the first of November for 10 weeks.

Please contact Dr Mirjalili for details of the project if you are interested.

Background

Lipid kinases are a small family of enzymes that allow a cell to respond to changes in its environment. In cancer, the gene encoding one of these proteins is mutated and produce a hyperactivated enzyme that promotes cancer cell growth and survival. Inhibiting the activity of the mutant enzyme is therapeutic in some cancers. Much of the discovery and development of inhibitors for these enzymes is around only a few compound classes.

This project will use computer based drug discovery methods to push the boundaries of what is possible in kinase inhibitor discovery and mine ultra-large virtual libraries of 10’s to 100’s of millions of compounds in quest to identify new types of molecules that could inhibit powerful oncogenic lipid kinase.

Skills

Computer based drug discovery skills that can be gathered from this project include :

• molecular docking
• ultra large virtual library screening
• use of high performance computing environment
• knowledge of structural biology
• chem-informatic analysis
• modular data-pipelines

To meet the learning needs of healthcare students, software simulations imitating real patients and clinical cases have become widespread in medical education. In interprofessional learning, simulations develop a wide range of non-technical skills in learners, including communication, teamwork and insight into others’ skills and roles.

Ready to Practice is a web-based software application enabling students to experience a critical and challenging emergency situation. It is written in HTML5 and JavaScript, along with the Monkey cross-platform scripting language. The current version is a single-user application.

The aim of this project is to extend the existing application to make it a multi-user environment. This includes developing a messaging system for the virtual patient environment, allowing an interprofessional team of students to care for the virtual patient, communicate through the application with each other, and send sms messages via the application.

Skills required

• HTML5, CSS, JavaScript (essential)
• Python (essential)
• Monkey X or Cerberus X (valuable)
• Django or other web-based frameworks (essential)
• Various web-based APIs and protocols (valuable)
• Server-side and front-end framework technologies (valuable)
• SQL and/or JSON (useful)
• Messaging services/APIs, SMS and/or email (useful)
• Understand security and develop a secure solution (useful)

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 repair following lymph node removal.

Almost nothing is known about how lymphatic vessels regenerate following injury. We have developed an in vivo assay of lymphatic vessel repair using either laser or mechanical ablation of fluorescently-labelled vessels in zebrafish. This project will utilise either pharmacological or genetic-based techniques to determine the roles of vascular signalling pathways in lymphatic repair.

Skills

• Model organism genetics
• Live cell imaging
• Zebrafish husbandry

Humans blink about 15,000 times a day, often more when wearing contact lenses. The repeated rubbing of the eyelids over plastic contact lenses produces known effects on the eyelids, but much less is known about the effects on the contact lenses themselves. Although the tears act as a lubricant to reduce the friction between the eyelid and lens, this lubrication can be inadequate. The proposed project investigates the degree to which contact lens wear is associated with debridement of plastic particles from the contact lens surface into the tears. Tears normally drain trough the puncta of the eyelid into the nasal cavities, where they come into contact with the nasal mucosa and then pass into the throat. The project aims to collect tear samples from contact lens wearers and non-contact lens wearers (controls) and to use a variety of laboratory techniques to detect the presence and characterise the sizes of plastic particles in the two groups.

Skills that will be acquired during the project:

• Recruit participants and take samples of tears
• Use a variety of laboratory methods to identify and characterise plastic microparticles in the tear samples
• Survey the relevant literature

Background

Overactive T-cells are involved in autoimmune disease, and blocking T-cell receptor function is one way to harness them. The protein kinase Lck is central to activation of the T-cell receptor making it an opportunity for therapeutic intervention using small molecule inhibitors. The only caveat is that there are >500 kinases in the human genome, so inhibitors of this enzyme need to be highly selective. This is for two reasons, one is to avoid unanticipated effects of blocking other kinases, and the other is to define the therapeutic advantage of the target kinase by blocking it alone. In this project you will design and make new inhibitors that seek to selectively block Lck.

Skills

• synthetic chemistry
• structure activity relationship analysis
• structural biology relevant to drug design

New strategies, with limited costs and potential side effects, are needed for enhancing neurorehabilitation in a range of populations. Brief and repetitive exposure to hypoxic (low oxygen) air, so called “acute intermittent hypoxia” (AIH), has been shown to safely enhance neural plasticity and recovery following animal models of incomplete spinal cord injury. The purpose of this project is to explore whether AIH increases cortical excitability/plasticity, neurovascular coupling and motor performance in young healthy people using non-invasive techniques. These studies will provide novel scientific insights into the normal physiological responses in low-risk groups and lay the groundwork for future studies in clinical populations.

Applicants should have a strong interest in rehabilitation, applied physiology and working with human volunteer study participants. Preference will be given to students who wish to continue on with an Honours or a Masters project.

Skills developed during this studentship include:

• the collection of physiological data in conscious humans
• data analysis
• literature reviewing
• writing skills
• oral presentation skills

The candidate will collect samples of propofol from theatre during general surgery at Auckland City Hospital, and assess its propensity to become inoculated over the course of a case.

The vast majority of current anticancer therapies rely on the induction of DNA damage. Abnormalities in DNA repair pathways and cell cycle progression in cancer cells can drive genomic instability (accumulation of mutations). This can lead to tumour progression but also has been shown to fuel activation of the immune system when combined with immunotherapy. A better understanding of the cellular response to DNA damage will inform our knowledge of cancer development and will help in designing better treatments.

We invite a student to participate in a research project in this fascinating field of cancer biology. Particularly, the project will focus on a newly discovered player in DNA repair pathways, a protein called CYREN. We have found CYREN to modify cancer cell response to radio- and chemotherapy and we are currently exploring the underlying molecular mechanisms. This summer project will help to determine the exact role of CYREN in DNA repair and will provide experience in tissue culture with model cell lines (generated with CRISPR/Cas9 technology) and testing for genomic instability in these cells.

We have established the ability within our laboratory to conduct whole genome knockout screens in human cancer cells using CRISPR/Cas9 technology. Using this technology, we have conducted several forward genetic screens to identify genes that may contribute to resistance and sensitivity to various anti-tumour therapeutic agents, as well as tumour microenvironment (TME) stressors, such as hypoxia and nutrient deprivation. Analyses of these datasets have provided many candidate genes that may contribute to anti-cancer drug sensitivity and tolerance of TME stress. As part of this project, the student will be validating the importance of these candidate genes and their molecular pathways, through the use of cells harbouring single gene knockouts and/or small molecular inhibitors.

Techniques

• Mammalian cell culture including maintenance of cell lines and cell-based assays
• molecular biology techniques 

Spinal cord injury (SCI) affects between 130 and 180 New Zealanders each year and has a devastating impact not only on patients but on their families as well. Following the initial injury, secondary injury can occur both in the acute and chronic phase. The chronic phase of injury is characterized by a lasting inflammatory response which leads to the development of neuropathic pain and is inhibitory to axonal regeneration.

We have previously shown that blocking Connexin 43 (Cx43) a gap junction protein which forms gap junctions, allowing transfer of molecules between cells. After injury it can also form a hemichannel (half channels) directly to the extracellular space and release proinflammatory mediators directly to the extracellular space and promoting an inflammatory environment.

Given that Cx43 is a validated target, we are trialling a Cx43 hemichannel blocking drug to determine if it can reduce inflammation amd lead to functional improvement. This project will use immunohistochemistry in rat spinal cord tissue to determine the mechanism by which our treatment reduces inflammation. This work has potential to ultimately make a real difference for people living with spinal cord injury, through reducing neuropathic pain and potentially allowing for axonal regeneration and recovery to occur.

The human corneal endothelium is a single layer of cells lining the back of the cornea, the clear window at the front of the eye. It regulates the hydration status of the cornea. A major road block to true corneal regeneration is the inability of these cells to proliferate or regenerate in humans and the resistance of these cells to expand in culture. Corneal endothelial dysfunction results in corneal oedema, opacity, and loss of vision, for which full thickness or partial thickness (endothelial) corneal transplantation is the definitive treatment. In New Zealand, the limited supply of donor corneal tissue is the rate limiting step for corneal transplantation. New treatments for corneal endothelial diseases are required to overcome the current limitations of donor tissue supply.

The recent discovery of adult stem cells in the ‘Transition Zone’ (TZ) marks the beginning of exciting forage into their application for endothelial regeneration. Our team has successfully established a TZ explant culture protocol. TZ culture is a mixed population of more differentiated (corneal endothelial like) and less differentiated (stem cell like) cells. However, in order to advance this into an applicable therapy, better control of cell differentiation is required in order to avoid the risk of cancer formation from uninhibited proliferation of stem cells and allow the use of cells at earlier passages.

We aim to determine the potential of transition zone cells to be developed into cell therapies and tissue grafts for corneal endothelial diseases. We propose to drive the differentiation of TZ cells or use cell sorting to separate differentiated cells from stem cells as the first step. The differentiated cells will be delivered in ex vivo or in vivo models to determine their regenerative potential.

Key words

ophthalmology, eye, cornea, diseases, therapy, stem cells, regeneration

Skills learned

• Cell culture
• aseptic techniques
• immunohistochemistry
• data acquisition
• statistical analysis
• report writing
• presentation skills

Spinal cord injury (SCI) results in a devastating loss of mobility and other major functions for the victim. A key component of the injury is formation of the glial scar by astrocytes. This is a major barrier to functional recovery after injury, and as such is a promising target for treatments to improve outcomes. One approach that has shown promise for spinal cord injury is use of the bacterial enzyme chondroitinase ABC (ChABC), which is involved in breakdown of CSPGs. This has been shown to reduce inflammation and lead to axonal regeneration. However, chronic delivery of such agents carries risks of tissue damage and infection.

One safe way to allow continued production of protective molecules is to use viral vector gene therapy. AAV gene therapy is safe, well tolerated and has been shown to be safe clinically.

In our laboratory, we have made an AAV vector to express ChABC preferentially in astrocytes through use of a GFAP (astrocyte-specific protein) promoter and are currently testing in a rodent mole of SCI.

This project will use immunohistochemistry to determine if this treatment modulates inflammation following spinal cord injury, an important step in developing this approach as an effective treatment for patients.

Aims

Gout represents the most common inflammatory arthritis in New Zealand, with Maori and Pacific people showing one of the highest prevalence rates worldwide. Hyperuricemia leads to monosodium urate (MSU) crystal deposition in peripheral joints, which activates tissue-resident macrophages that drive neutrophil recruitment and acute local inflammation. Hyperuricemia can have a multitude of causes, one of which is a genetic predisposition, which favors the early development of gout. We recently established a unique zebrafish model of gouty arthritis in the lab, including a mutant zebrafish line of the gout susceptibility gene ATP-binding cassette subfamily G member 2 (abcg2a). Despite its role in gout and as a drug efflux transporter, little is known about why abcg2a is highly expressed on macrophages and how this contributes to a potential role in inflammation. This project will involve characterizing abcg2a’s role in zebrafish innate immunity using a Salmonella-GFP infection model.

Skills

• Transgenic and mutant fish lines (husbandry, handling and screening)
• Live cell imaging
• Genetics
• Molecular Biology
• Whole-mount in situ hybridization
• qPCR

Gene therapy is a promising treatment approach for Parkinson's disease (PD), the second most common neurodegenerative disorder. We are developing a gene cocktail approach for PD that involves expressing proteins and gene sequences that target multiple pathways proposed to contribute to the demise of the vulnerable dopamine neurons that progressively die in PD. The aim of this project is to contribute to our program of research that involves characterising and optimising components of this gene therapy cocktail.

This project would be suitable for a student looking to go onto complete an Hons or Masters in this research area

Skills taught

• mammalian tissue culture
• transfection
• western blotting
• immunocytochemistry
• imaging

Skills required

Motivated students with previous wet lab experience preferred. 

The brain possess critical regulatory mechanisms to ensure adequate compensatory blood vessel dilation and increased perfusion (known as “cerebrovascular reactivity”). Cerebrovascular reactivity is impaired in a number of cerebrovascular diseases and neurological disorders, and is an established independent predictor of cardiovascular mortality. Magnetic resonance imaging (MRI) using arterial spin labelled (ASL) perfusion is a state-of-the-art approach for non-invasively acquiring whole brain blood flow images by using water in arterial blood as a tracer. The purpose of this project is to establish a new approach for assessing cerebrovascular reactivity using ASL at the University of Auckland, that can be applied to a clinical population.

The studentship will provide an opportunity to gain an understanding of how MRI images are acquired/processed, insights into human brain physiology, experience of working with human participants in a clinically relevant context, along with general literature reviewing, writing and oral presentation skills.

Relevant skills or experience with the following would be advantageous:

• MATLAB/Python
• image processing
• data analysis
• working with human volunteer study participants

Aims

Hearing loss is the greatest cause of sensory disability, affecting over 5% of the world’s population. Acute insult to the ear, such as from overexposure to sound, infections, ototoxic drugs or hypoxia/ischemia may result in damage to the inner ear sensorineural tissues and hearing loss. There are limited treatment options for sensorineural hearing loss (SNHL) other than hearing aids and, in extreme cases, cochlear implants. Hearing aids boost residual hearing functionality, but these have limitations because the ear still remains damaged.

This study aims to develop novel adenosine receptor-based treatment strategies to repair the cochlea and prevent hearing loss after injury. This strategy is based on inhibition of the molecular complex (RGS4-neurabin) that terminates adenosine A1 receptor (A1R) signalling, thus increasing the A1R responsiveness to endogenous adenosine.

Skills

Quantitative histological techniques will be used in this study to assess the loss of sensory hair cells, spiral ganglion neurons and afferent synapses. Techniques acquired during this studentship include cochlear dissection, immunohistochemistry and confocal/epifluorescence microscopy.

During human IVF the embryo is checked during development to identify aspects of morphology which indicate embryo quality. One such aspect of morphology that has been understudied is ‘excluded cells’ which are cells that become unincorporated during development. As the embryo transitions from the cleavage stage to the blastocyst stage, some cells may become excluded from the embryo, potentially representing a loss of genetic and cytoplasmic material. Whether these excluded cells correlate to the developmental potential of the blastocyst is unknown, as it is difficult to visualise the cells behind the expanding blastocyst. Once the blastocyst is collapsed after freeze-thawing however, excluded cells can be observed to determine their significance to developmental potential.

The aim of the project is to study the frequency of excluded cells in the blastocyst, and their relationship to onward development (ongoing pregnancy) using images following freeze-thawing. Excluded cell pattern and size will be quantified and correlated to blastocyst quality and pregnancy outcomes.   

Recent advances in optogenetics allow us to stimulate individual brain cells using light to probe neural networks with unprecedented precision. The cutting-edge optogenetic approach called channelrhodopsin assisted circuit mapping (CRACM) has been established in the laboratory of Dr Freestone where it is used to discover the organization of the neural network within the brain structure called the subthalamic nucleus. This part of the brain is vital to normal execution of movement, and becomes hyperactive in the neurodegenerative disorder Parkinson’s disease, highlighting the importance of studying this network in detail.

The project would establish a framework for combining functional network information (acquired from CRACM experiments) with detailed 3D anatomical reconstructions of the whole subthalamic nucleus. Advanced tissue clearing (CLARITY) and microscopy techniques developed at the Auckland Bioengineering Institute (Dr Mark Trew) will be used to generate these whole nucleus reconstructions from thick brain tissue slices.
There are opportunities for continued study at Honours, Masters, and PhD level.

Congenital heart disease is the most common birth defect. Due to improvements in surgical techniques those with congenital heart disease are living longer, and the population of adults with congenital heart disease is now larger than the pediatric population. Magnetic resonance imaging (MRI) scans are now routinely used to monitor the changes to the heart in these patients. MRI is a versatile imaging modality that can provide information on heart structure, tissue properties, and function. A better understanding of the relationship between heart structure and function in these patients is an important step in developing future treatment options and ensuring these patients have a longer and healthier life.

In this project you would work with MRI images from patients with congenital heart defects to better understand the relationship between heart structure and function in these patients. Students will gain an understanding of MRI scanning techniques, and develop skills in image processing and data analysis.

We recently characterised genomic changes (point mutations, loss-of-heterozygosity and chromosomal aneuploidy) that correlate with patient prognosis in pancreatic neuroendocrine tumours (pNETs) (Lawrence et.al. 2018, npj Genomic Medicine). A fundamental need emerging from this study is to identify cellular pathways that dictate response to the standard chemotherapy regime for pNETs. The summer studentship will generate tools and data to answer this question. To tackle this aim in a controlled manner, we will focus on a cellular model of pNET and perform genome editing on genes of interest like DNA repair enzymes (e.g. MGMT). This will yield a cell line panel with genotype defined gene dosage that will be treated with temozolomide and/or capecitabine and assayed for functional outcomes such as cell viability and/or apoptosis. Additionally, gene expression analysis (RNA and protein) will be performed to characterise the biological pathways that mediate sensitivity/resistance to chemotherapy.

The student will be embedded within a research group, with experts on genomics and cell and molecular biology working alongside clinicians. The studentship is part of a broader programme of research on the genomics and cell biology of neuroendocrine tumours.

Techniques covered will include:

• cell culture
• CRISPR/Cas9 mediated genome editing
• Sanger sequencing
• qPCR and Western blotting

Bone has a tremendous healing capacity, and fractures generally heal to restore the original functionality of the bone. However, in severe cases, or in patients who are elderly or have other complications healing may be delayed or blocked. The periosteum is a rich source of stem cells that go on to form bone, however, there are no well-established ways to identify these cells. In addition, the processes by which they activate and differentiate are also poorly defined. The goal of this project is to examine how cell populations change in the periosteum after injury. This will be done using flow cytometry, immunostaining and histology. This project will cover a defined area related to the question to be determined by the PI together with the student.

You will perform or be exposed to techniques including: cell culture, tissue dissection, flow cytometry and cell sorting, immunohistochemistry, image analysis.

Hands on experience in some lab techniques preferred. Students who are considering continuing with a research-based degree (Honours or Masters) are particularly encouraged to apply.

Preptin is a peptide discovered in New Zealand. We have recently generated a novel knockout mouse model. Our preliminary data indicate that the knockout mice have increased bone volume. At present, we do not know the mechanism for this change. This project would involve further evaluation of preptin distribution in normal mice, and bone cells in knockout mice. This would include evaluating preptin expression in bone tissues and other tissues by immunostaining and real-time PCR. Differences in expression of genes important for bone cell function between bones from WT and KO animals can also be tested. Primary cell cultures from knockout and wild-type mice can be used to evaluate bone cell activity when cells are removed from the mice. These assays would be used to test growth and differentiation of mesenchymal progenitor cells from WT and KO animals.

Techniques potentially include:

• animal handling
• genotyping and colony management
• primary cell isolation and culture
• bone marrow stromal cell differentiation into osteoblasts and adipocytes
• real time PCR
• histology and immunostaining

Hands on experience in some lab techniques preferred. Students who are considering continuing with a research-based degree (Honours or Masters) are particularly encouraged to apply.

Pancreatic cancer (PC) is the most lethal cancer. Clinically, nanomedicines have been shown to have the highest accumulation in PC among all types of tumours. However, after entering cancer cells, nanomedicine may be entrapped in endosomes, limiting the drug availability to their target.

In the previous study [1] we developed gemcitabine-loaded pH-sensitive liposomes (150 nm) with superior abilities for cellular uptake, ‘endosomal escape’, and in vivo tumour growth inhibition in animals. Recent researches have indicated liposomes in the range of 60-100 nm could achieve better biodistribution in tumours. Herein, we aim to investigate the ability for ‘endosomal escape’ of liposome of smaller size in cell culture model.

Specifically, we aim to:

1. Prepare pH-sensitive liposomes of different size (150 vs 50 nm) [1].
2. Pompare the liposome size on their drug release in vitro, cellular uptake, endosomal escape and cytotoxicity to PC cancer cell line.

For students who are interested: please note this project is only available to Part II and Part III BPharm students as this project is being provided by the NZ Pharmacy Education and Research Foundation (NZPERF).

Research in mice has demonstrated changes in fluid fluxes across the brain that predominate during sleep – a postulated night-time “wasted disposal system” for the brain. Whether this also occurs in the human brain is the subject of this research. We have collected high resolution diffusion MRI data from normal human volunteers as a new way to interrogate how the brain change during sleep. The summer studentship will involve analyzing these data for microstructural changes in the human brain that accompany sleep. Previous experience with MATLAB, data analysis and image processing tools such as FSL or AFNI would be very helpful.

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. 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 modelling
• data analysis

Background

Prostheses for valve replacement surgery have each faced some limitation precluding their routine clinical-use. Thus, decellularised heart valves have been investigated as an alternative product.

Decellularised heart valves are created from tissues of animal origin, such as pericardium or valvular leaflets, which are subjected to a chemical treatment protocol to remove the genetic material of the donor animal. This protocol leaves behind a connective tissue scaffold that can be either directly implanted as a valvular conduit or first reseeded with living cells to facilitate conduit growth, repair and remodelling after implantation.

We are conducting a project in which we are tissue engineering a novel decellularised heart valve. A component of this project involves examining the immunogenicity of the product using a live animal model.

Project

The project will commence by conducting a systematic review of the literature. Animal handling and surgical skills will be learnt using rat cadavers and then employed to develop a subcutaneous rat model with which analyses of conduit immunogenicity can be conducted in future. It is anticipated that the work will culminate in the submission of at least one publication for peer-review.

Skills

• Systematic review
• Academic writing
• Valvular anatomy
• Animal handling
• Surgical instrumentation
• Surgical skills

Brain injury as a consequence of oxygen deprivation while in utero or at birth is very common in premature infants. In addition to its contribution to mortality, it can lead to devastating lifelong effects on neurodevelopment, with increased risks of cerebral palsy, mental retardation, and cognitive deficits. Currently, no effective therapeutic strategies are available to prevent or improve the outcome of preterm infants with brain injury.

Our studies using a well-established animal model of preterm brain injury suggest for the first time that delivery to the brain of a therapy that manipulates a critical endogenous neuroprotective anti-inflammatory mechanism can reduce damage to specialised cells, called oligodendrocytes, which produce a fatty substance called myelin that electrically insulates neurons enabling efficient transmission of electrical brain waves. These findings suggest that it is possible to preserve these myelin-producing cells by supporting natural pathways in the brain.

This summer studentship project will seek to establish whether this therapy has a sustainable effect on survival of these myelin-producing oligodendrocyte cells following injury. The project ideally suits students with a strong background in neuroscience and physiology who are considering undertaking an Honours or a MSc project.

Skills

• Immunocytochemistry and immunofluorescence analysis
• Data collection and statistical analysis
• Literature review
• Report writing
• Presentation of results 

Oxygen deprivation occurring in the womb or during delivery leads to permanent functional impairment of the brain and is one of the most common challenges faced by infants born preterm. Currently, there are no effective therapies to reduce injury. A major therapy limitation is the failure to traverse the blood brain barrier (BBB) and enter the brain. Exosomes, small vesicles, are naturally capable of penetrating the BBB, and have the capacity to communicate with the microenvironment through transfer of proteins, miRNA and other nucleic acids. Importantly, they have an intrinsic neuroprotective therapeutic activity as well as being ideal candidates to deliver targeted therapeutic molecules of choice. Evidence suggests generation of neural stem cell-derived exosomes would be more likely to exhibit the highest distribution to the brain and confer neuroprotective benefits. A vital step to moving forward with our investigations to test the efficacy of this therapeutic option is to first generate sufficient exosomes from cultured neural stem cells and characterise them.

The aims of this project are therefore to prepare, purify and characterise exosomes from human fetal neural stem cell-conditioned culture media.

Skills required or acquired during the project:

• cell culture
• size-exclusion chromatography for isolation of exosomes
• Nanoparticle tracking analysis
• western blot analysis

Heart disease is the leading cause of morbidity and mortality in diabetic patients. In diabetes, cardiac complications are evident even in the absence of vascular abnormalities and represent a primary manifestation of the disease. Understanding the mechanisms of cardiac pathology in diabetes is important for the development of new targeted treatment therapies. We have recently reported that a particular type of programmed cell death, autophagy, is upregulated in diabetic hearts but an understanding of how autophagy contributes to cardiac pathology in diabetes is lacking. Preliminary evidence suggests that the disturbed balance of systemic glucose, fructose and insulin levels in diabetes modifies key signaling pathways involved in autophagy induction. This project aims to investigate the molecular mechanisms underlying heart dysfunction in diabetes.

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 intracellular organisation of the calcium signally apparatus that controls contraction.

In this project you 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.

Mimopath technology was developed as a display system that allows high efficient immobilisation of heterologous proteins on bacterial surfaces, in applications such as mucosal vaccines where genetically modified bacteria is less desirable. The technology utilises the binding domain of the Lactococcus lactis peptidoglycan hydrolase AcmA, which exhibits high affinity to the bacterial peptidoglycan. We proposed that this protein anchor (PA) domain can be used as a protein tag that is fused to a recombinant protein. Heat and acid treated L. lactis cells, also known as bacteria-like particles (BLPs), can be used to purify PA fusion proteins.

This project will explore the construct design of a PA tag protein expression vector, and optimise the procedures of this novel purification method. The efficiency of this system will be compared to conventional affinity protein purification techniques, such as the GST tag or poly Histidine (6xHis) tag. It is expected that this novel application of the Mimopath technology will offer a simple, fast and economical method for recombinant protein purification, which is an essential part for both basic scientific research and biomedical applications.

Skills

• Molecular cloning
• recombinant protein expression and purification
• microbiology techniques
• protein analysis techniques such as electrophoresis (SDS-PAGE)

The student will be based at the Infection and Immunity Lab of the Department of Molecular Medicine and Pathology, University of Auckland.

Choose the methodology of a systematic or Integrative review. Use a clear and precise search and selection criteria which is described clearly so that another researcher can duplicate the searches and the study selection. From this review (a) analyse and compare articles, identify themes and determine gaps in the current research, and draw conclusions. (b) Where applicable identify evidence based practice and describe how this can be incorporated into clinical practice.

Choose the methodology of a systematic or Integrative review. Use a clear and precise search and selection criteria which is described clearly so that another researcher can duplicate the searches and the study selection. From this review (a) analyse and compare articles, identify themes and determine gaps in the current research, and draw conclusions. (b) Where applicable identify evidence based practice and describe how this can be incorporated into clinical practice.

Cannabinoid Receptor 2 (CB2) is a G Protein-Coupled Receptor (GPCR) expressed primarily in the immune system and CB2-targeted drugs are promising therapeutic leads in a wide range of disorders involving immune system dysregulation, including multiple sclerosis, autoimmune disorders, atherosclerosis, stroke and inflammatory bowel disease.

While traditionally thought of as distinct functional units, it is now well recognised that GPCRs can interact with multiple different proteins which may influence their function – either by altering their subcellular distribution and expression level, or by modulating their conformational states and thereby their signalling properties. Further understanding of these interactions is critical to research on receptor function, as well as being highly illuminating in prospective therapeutic design. Importantly, differential expression of such interaction partners is a means for a receptor to have different effects between cell types, and dysregulation of interaction partners may result in disease.

This project will investigate a set of proteins that have been suggested (in the literature or in our pilot experiments) to interact with CB2. We will utilise over-expression and/or knockdown to determine the effects of these putative interacting proteins on CB2 subcellular localisation and signalling.

There are opportunities for continued study at Honours, Masters, and PhD level.
Profile: Natasha Grimsey

Cannabinoid Receptor 2 (CB2) is a G Protein-Coupled Receptor (GPCR) expressed primarily in the immune system and CB2-targeted drugs are promising therapeutic leads in a wide range of disorders involving immune system dysregulation, including multiple sclerosis, autoimmune disorders, atherosclerosis, stroke and inflammatory bowel disease.

We are particularly interested in studying functional selectivity, wherein a single GPCR has the potential to mediate the activation or inactivation of diverse signalling pathways and each molecule that interacts with the receptor has the potential to induce a unique ‘fingerprint’ of signalling events within the cell and thereby induce different functional consequences. An emerging concept in functional selectivity is that of spatio-temporal modulation, wherein the location of the receptor and/or induced signal may give rise to unique downstream effects.

This project will investigate the spatio-temporal signalling profiles of a selection of CB2 ligands which have been suggested to give rise to distinct signalling and/or functional profiles. We will utilise cutting-edge signalling pathway biosensors that allow real time measurements of signalling in specific subcellular locations.

There are opportunities for continued study at Honours, Masters, and PhD level.
Profile: Natasha Grimsey

N-methyl-D-aspartate (NMDA) receptors play a central role in brain development and function and contributes to the pathogenesis of many neurological diseases. We have developed an antibody-based strategy for selectively amplifying the activation of NMDA receptor-mediated signaling pathways that promote neuronal survival and learning and memory. An immunotherapy that has both cognitive-enhancing and neuroprotective properties would have broad therapeutic utility against a broad range of neurological disorders in humans.

We are currently testing the therapeutic effectiveness of our immunotherapy to determine whether our therapy can prevent the decline in learning and memory function that occurs in aged mice.

This summer studentship project will involve biochemical and molecular analyses of the brains of treated aged and adult mice to examine the effect of the treatment on NMDA receptor expression and downstream signalling molecules.

Skills taught

• tissue processing
• western blotting and/or ELISA

Digital drop or real time qPCR approaches may also be used for this project.

Skills required

Students with some previous lab experience are preferred. This project may be suitable for a student looking to go on to do an Hons or Masters project. 

As we age vascular function tends to deteriorate, which in turn increases the risk of cardiac disease and strokes. This project will look at how vascular function changes during the development of heart failure. This study will use a rat model of heart failure, and repeated ultrasounds will be used to assess blood flow changes to the kidney over time, and determine the responsiveness of the vasculature in response to hypercapnia/hypoxia. The first step in this project will be to establish reliable methodology. Once the methodology is established we will then examine potential options to alter the progression of the changes in function.This project will introduce the student to a number of experimental techniques in a rat model. Preference will be given to students who want to continue on with an Honours or a Masters project.

Skills taught and mentored during this studentship include:

• Literature review writing skills
• Basic surgical and ultrasound skills
• Collection of physiological data
• Analysis of data
• Oral presentation skills

Growing Up in New Zealand is a longitudinal study that provides a contemporary, population-relevant picture of what it is like to be a child growing up in New Zealand in the 21st century. Participants (n=6853) were recruited before birth through their pregnant mothers, with 6156 children participating in the 4 year interview. Throat swabs were collected and microbiological analyses conducted to determine staphylococcus aureus and streptococcus pyogenes colonisation when the children were four and eight years of age.
The aim of this project is to explore environmental factors associated with bacterial colonisation and how colonisation is related to child health outcomes. This will be achieved through quantitative analysis of questionnaire and microbiological data collected from the children.

Skills taught

This project will provide an opportunity for a student interested in population health or child health to learn independent research skills, including:

• Literature review
• Data analysis 
• Presentation of results and communication of research findings

The project would most suit a third year student, especially someone interested in continuing with an honours project. Second year students will also be considered. Skills required are enthusiasm and initiative, an ability to communicate, and independence, combined with a genuine interest in research and a demonstrated ability to work in a team environment.

There is rapidly growing interest in extracellular vesicles (EVs) and their potential role in biology and medicine. The EVs produced by most cells/tissues are separated by size into nano-vesicles (including exosomes), micro-vesicles and macro-vesicles. During pregnancy, large quantities of placental EVs are extruded from syncytiotrophoblast into the maternal circulation. These EVs contain proteins and nucleic acids and could contribute to the mal-adaptation of maternal immune and vascular systems to pregnancy.

A large number studies have shown that in the pathological conditions, placental EVs contain increased danger signals and vasoactive substances. Our previous studies showed that mitochondria and caspase pathway are involved in this process. However, the underlying mechanism of this process has not been well investigated. Therefore in this study, we aim to investigate how caspase pathway, in particular caspase 8 is involved in placental EVs extruding from placental syncytiotrophoblast.

The aims of this project are to investigate (1) blocking caspase 8 pathway could affect the nature of placental function by measuring endoplasmic reticulum stress, total MLKL levels and the concentration of placental EVs that are extruded from first trimester placenta in both physiological and pathological conditions. (2) Whether other potential molecules are also co-ordinated with caspase 8.

Skills

• Cell and tissue culture
• Western blotting
• Immunohistochemistry
• General laboratory skill

Children and young people in New Zealand receive varying degrees of mental health/wellbeing education and preventative interventions at primary and high school. However, the evidence base regarding the most appropriate school-based interventions that should be delivered by schools is currently unclear.

This summer student project involves conducting a systematic review of the literature to identify evidence-based school-based mental health interventions that could inform more coherently delivered mental health education in schools.

The successful student would be guided to conduct such a review and summarise the results. They would also be listed as an author on the resulting paper.

As most of the activity on this project will be conducted online or on a computer, the student would be able to undertake most of the required work in a flexible manner, either within the university or elsewhere, allowing for some vacation time over the Christmas period.

Complementing this project will be a national survey or qualitative study of school-based health practitioners. Both pieces of research will hopefully inform the development of new mental health/wellbeing resources for schools.

The ocular lens of the eye is a remarkable tissue in that it is able to maintain its transparency over many decades of life. This is due to the highly structured cellular architecture of the lens comprised of cuboidal lens epithelial cells and elongated fibre cells. Lens fibre cells are derived from epithelial cells through processes of proliferation and differentiation. Numerous studies published from our laboratory have shown that differential expression and trafficking of proteins in epithelial cells and mature fibre cells are critical for maintaining the lens transparency.

Lens epithelial cells can be cultured and induced to differentiate into fibre cells in vitro. This project aims to establish a new experimental protocol for culturing rodent lens epithelial cells as a platform for manipulating gene expression in these cells and monitoring them live. The participating student will prepare rodent lens epithelial cell explant culture, transfect with fluorescent fusion proteins and monitor expression and trafficking of proteins.
The successful applicant should have a basic background in biology and physiology. Interest in postgraduate research programmes will be preferable, but not essential.

Skills the student will learn

• Tissue dissection and culturing
• DNA transfection
• Fluorescent and Confocal microscopy
• Image analysis and scientific report writing

Our sense of hearing starts in an inner ear organ called the cochlea containing ciliated hair cells, supporting cells and neurons. Hair cells are primary auditory sensory cells and their death results in sensorineuronal deafness. In addition to hair cells, there are eight different types of supporting cells arranged in highly ordered architecture within the cochlear sensory epithelium. While these supporting cells are emerging as key players in cochlear pathology, much remains unclear about their precise roles, development and how they respond in early phases of neurotoxic injuries.

Previous studies in our laboratory have found transient expression of a group of purinergic receptors in supporting cells during development, but the reason is not known. To investigate this further, this project aims to identify different types of supporting cells in developing cochlea, and characterise purinergic receptor expression in each cell type. Participating student will be conducting hands-on laboratory work from dissection of rodent cochlea, immunohistochemistry and microscopy.

The successful applicant should have a basic background in biology and physiology. Interest in postgraduate research programmes will be preferable, but not essential.

Skills the student will learn

• Fluorescent microscopy
• tissue dissection
• immunohistochemistry
• confocal microscopy
• image analysis
• scientific report writing

The brains of dolphins have striking resemblance to humans, in both size and structure, and it would appear that much of their function parallels human function, including language processing. The dolphin being a long-lived, large brained mammal, is proving to be an unexpectedly useful model for the study of human ageing and dementia. The development of a high resolution atlas based on 3D MRI imaging to act as a road map for future studies such as additional DTI and functional MRI studies, is a vital first step to moving the field forward. The MR imaging data for this project has been acquired and has already been part segmented.

Skills acquired during the project

• in depth knowledge of neuroanatomy (human and dolphin) 
• data segmentation

Suitable project for neuroscientist or medical student. Envisioned outcome: publication of atlas as a paper.

References:
Wright A, Theilmann R , Ridgway S, Scadeng M. Diffusion tractography reveals pervasive asymmetry of cerebral white matter tracts in the bottlenose dolphin (Tursiops truncatus) Brain Struct Funct. 2017 DOI : 10.1007/s00429-017-1474-3

Wright A, Scadeng M, Stec D, Dubowitz R, Ridgway S, Leger JS. Neuroanatomy of the killer whale (Orcinus orca): a magnetic resonance imaging investigation of structure with insights on function and evolution. Brain Struct Funct. 2017 Jan;222(1):417-436. doi: 10.1007/s00429-016-1225-x.

Regeneration and healing involves generation of new tissue that includes vasculature and innervation. The role of peripheral sensory neurons that innervate healing bone is poorly defined. The periosteum, a critical source of new osteoblasts during fracture repair, is the most densely innervated bone compartment. Despite indications that sensory innervation promotes growth, maintenance and healing of bone, the underlying mechanisms are poorly understood. CGRP is a strong candidate mediator of these effects. We have an established colony of CGRP knockout mice.

The goal of this project is to evaluate how CGRP affects bone healing and the signalling mechanisms associate with this. Projects could involve evaluating bone healing, innervation and vascularisation using an injury model, in knockout and wild-type mice; investigating changes in CGRP knockout periosteum in the absence of injury; in vitro investigation of CGRP signalling mechanisms in bone cells.

Techniques potentially include:

• primary cell isolation and culture
• real time PCR
• western blotting
• histology and immunostaining
• animal surgery
• microCT

Hands on experience in some lab techniques preferred. Students who are considering continuing with a research-based degree (Honours or Masters) are particularly encouraged to apply.

Motor neuron disease is a fatal and incurable movement disorder affecting ~1 in 15,000 New Zealanders. The brain tissue of people with motor neuron disease harbours aggregated proteins, the formation of which is likely to be neurotoxic. This project seeks to use cultured cells expressing mutant versions of these aggregating proteins, together with small interfering RNAs, to test the molecular requirements for protein aggregation and disposal. By determining how protein aggregation is seeded and reversed in motor neuron disease, we hope to determine an upstream therapeutic target for sidestepping the protein aggregation process.

Further details available at a later date.