Positive reintegration of ex-prisoners’ focus of HRC grant project

Improving the health and wellbeing of Māori who re-enter society from prisons, alongside their whānau and communities, is the aim of a University of Otago project which received Health Research Council of New Zealand funding today.

The Kaupapa Māori project was awarded a $2 million Māori Health Project grant, one of 22 Otago projects which received nearly $34 million in HRC Project and Programme funding.

Paula King image

Dr Paula King

Co-led by Dr Paula Toko King (Te Aupōuri, Te Rarawa, Ngāpuhi, Ngāti Whātua, Waikato Tainui, Ngāti Maniapoto), of the Eru Pōmare Māori Health Research Unit, Dr Ruth Cunningham of the Department of Public Health, Wellington, and Cheryl Davies (Ngāti Raukawa, Ngāti Wehi, Ngāti Mutunga o Wharekauri) from Kōkiri Marae, the project will focus on community re-entry wellbeing.

“Māori have been incarcerated on a mass scale – a legacy of colonisation and coloniality. We are coming to understand the adverse and inequitable health and wellbeing impacts of mass incarceration, including as a driver of health and social inequities.

“These impacts are not limited to the period of incarceration itself but extend into the period after release. Many who enter and leave places of incarceration experience health and social inequities compared to the general population.

“Community re-entry presents an opportunity to understand and better address the health and wellbeing impacts of incarceration on Māori individuals, their whānau and communities,” she says.

Using routinely collected government data, the project team will aim to better understand community entry pathways for Māori, and factors which influence wellbeing outcomes after release. Whānau with lived experience of incarceration will also be supported as qualitative researchers to develop self-determined positive pathways.

“We hope this work will draw attention to an underexplored area, raising awareness around the links between the justice system and Māori health inequities, for the public to have broader conversations about the justice system.”

Two other large grants, of just under $5 million over 60 months each, went to Professor Lisa Stamp, of the Department of Medicine, Christchurch, and Professor Haxby Abbott, of the Department of Surgical Sciences.

Professor Stamp will use the funding to investigate strategies to improve gout management in Aotearoa.

Gout is particularly prevalent in Aotearoa, with 13.8 per cent of Māori men, 22.5 per cent of Pacific men, and 6.9 per cent of Pakeha men affected. Effective management of gout involves lowering blood uric acid level to a treatments target, usually with a medication called allopurinol. However, the current strategy for increasing allopurinol to achieve the target is time consuming and difficult to implement.

An easier way to use allopurinol is required so the aim of the research programme is to determine whether a different delivery is as effective as the current one.

Professor Abbott aims to reduce the nation’s burden of osteoarthritis, as well as shine a light on what he believes is an under-acknowledged, under-resourced and under-researched health problem.

As one of the most common long-term conditions in Aotearoa, the burden of pain, disability and economic costs associated with the condition is rising – especially for Māori.

This programme of research will look at ways to deliver the best value for money and equity in managing osteoarthritis in the New Zealand public healthcare system, from prevention through to joint replacement surgery.

Rural health research also got a boost with two Otago projects funded to improve services in rural areas.

Dr Rory Miller, of the Department of General Practice and Rural Health, will assess a pathway to allow patients who develop chest pain to remain closer to their communities and whanau by accessing blood testing technology which is as accurate as those available in urban emergency departments.

Associate Professor Garry Nixon, of the Department of General Practice and Rural Health, is seeking to better understand the impact of rurality on health outcomes and healthcare delivery.

Aotearoa has not undertaken much research into the health status of rural communities, so he wants to find out how rurality, ethnicity and socioeconomic status interact to impact on health outcomes and access to health services for New Zealanders, how people move between urban and rural areas when they become unwell, and how much public healthcare rural New Zealanders consume, in dollar terms, compared to their urban compatriots.

Deputy Vice-Chancellor, Research and Enterprise Professor Richard Blaikie is pleased with the funding received from HRC and knows it will lead to findings which will have an enduring impact on the health and wellbeing of New Zealanders.

“The treatments and interventions that come from this research will also reduce the costs of care and significantly reduce inequities in our health system in many cases.

“We are extremely grateful that the Health Research Council has again been able to support some of our best and brightest research teams in their endeavours in this year’s round.”

HRC 2022 Project and Programme grant recipients

Programme recipients:

Professor J. Haxby Abbott, University of Otago

Reducing the Burden of Osteoarthritis in Aotearoa New Zealand

60 months, $4,999,268.10

Osteoarthritis is among the most common long-term conditions in New Zealand. The burden of pain, disability and economic costs is rising – especially for Māori. Access to treatments is poor. Joint replacement surgery is highly cost effective, but demand – already straining capacity – is growing rapidly. Cost-effective interventions for early- and mid-stage osteoarthritis are known to have good outcomes and are potentially cost-saving compared to current practice, but are not being delivered. Multimorbidity is common. Coping with future demand will require optimising resource allocation; we must consider preventive measures and coordinated delivery of accessible, equitable, effective and cost-effective interventions. This programme of research of four linked multi-disciplinary projects will look at ways to deliver the best value for money and equity in managing osteoarthritis in the NZ public healthcare system, from prevention through to joint replacement surgery.

Professor Lisa Stamp, University of Otago, Christchurch

Strategies to improve gout management in Aotearoa

60 months, $4,998,486.21

Gout is particularly prevalent in Aotearoa/NZ, with 13.8% of Māori men, 22.5% of Pacific men, and 6.9% of NZ European men affected. Effective management requires lowering the blood urate level to a treatment target, usually with a medication called allopurinol. There are important inequities based on ethnicity in allopurinol prescribing in Aotearoa. The current best practice treatment strategy is time consuming and difficult to implement. An easier way to use allopurinol is required, especially since gout disproportionately affects middle-age men who are frequently working and are not able to take time off work or afford the costs involved with the current strategy. The aim of this Programme is to determine whether a protocol[1]driven allopurinol dose escalation strategy based on the dose predicted to achieve target urate is as effective as the current best practice intensive treat-to-target strategy.

Project recipients – General:

Professor Wickliffe Abraham, University of Otago

Neuron-glia regulation of plasticity in health and neuroinflammatory diseases

36 months, $1,197,310.48

Plasticity at synaptic junctions between nerve cells is fundamental to learning and memory. Such plasticity is generated not only by nerve cell activity, but it is also highly regulated by activity in nearby non-neural cells. In neurodegenerative diseases such as Alzheimer’s disease, the non-neural cells become pathologically reactive and drive brain inflammation. This unfortunately not only impairs synaptic plasticity and cognition, but it also amplifies the disease neurotoxicity when prolonged over time. Here we will study how non-neural cells work together with nerve cells to regulate synaptic plasticity normally in a brain region important for memory. Moreover, we will explore whether these mechanisms are aberrantly engaged in mouse models of frontotemporal dementia and multiple sclerosis, and whether a drug that reduces inflammation can rescue plasticity and memory to normal levels in these models

Dr Rosemary Brown, University of Otago

Hormones and mood: Imaging the impact of obesity on maternal neural circuitry

36 months, $1,199,908.32

Healthy mother-infant interactions are critically important for a child’s development. We have previously reported that the pituitary hormone prolactin plays a critical role in promoting care-giving behaviour in mothers, however, the underlying mechanism is unknown. The aim of this project is to determine how prolactin alters the activity of neurons that drive mood and behavioural changes in mothers. We will utilise recent technical developments in neuroscience to enable real-time recording of activity of prolactin-sensitive neurons during interactions with offspring. Maternal obesity is associated with an increased risk in developing a range of pregnancy complications, including postpartum mood disorders, and is also one of the primary causes of reduced prolactin signalling during pregnancy. Therefore, we will also investigate how obesity affects the activity of key populations of prolactin-sensitive neurons that regulate a mother’s behaviour during pregnancy and lactation.

Dr Tim Chambers, University of Otago, Wellington

The impact of nitrate in drinking water on preterm birth

36 months, $1,199,508.73

This research will investigate the association between nitrate in drinking water and preterm births. We will conduct a retrospective cohort study using a national cohort of births from 2009-2021 (~700,000) to assess the impact of prenatal exposure to nitrate in drinking water on preterm births. We will also include a within-mother study design where only consecutive children from the same mother are included in the analysis providing additional control for confounding by maternal factors. We will use the Integrated Data Infrastructure (IDI) to build the cohort and provide individual-level data on key confounders. Nitrate exposure via drinking water will be assessed through collation of testing results and spatial data on water supply boundaries from registered water supplies. Nitrate concentrations for all unregistered supplies will be modelled using existing environmental monitoring, geophysical and land use datasets.

Professor Catherine Day, University of Otago

WNT signalling – a matter of degradation

36 months, $1,199,533.94

In healthy animals, cellular processes precisely determine the number and type of cells. One pathway, referred to as WNT signalling, is required for embryonic development and maintaining adult stem cells. Abnormal activation of WNT signalling frequently leads to cancer, with mutations commonly occurring in the core pathway regulators. Two related enzymes, called ZNRF3 and RNF43, regulate WNT signalling by determining the abundance of WNT receptors on cell membranes. This is achieved by the attachment of a tag, called ubiquitin, which signals for the destruction of the receptors. Our goal is to identify new interventions for cancer by elucidating how ZNRF3 and RNF43 function. We will use biochemical approaches to reveal how these enzymes attach ubiquitin to WNT receptors and how they are regulated. This work will reveal important new knowledge about WNT signalling and should provide new targets for drug development.

Dr Jack Dummer, University of Otago

Development of rifampicin as a dry powder inhaler for tuberculosis

36 months, $1,086,230.65

Tuberculosis causes over ten million infections and over one million deaths each year. Treatment requires a long course of multiple antibiotics and is suboptimal: poor adherence, side effects, antibiotic resistance and treatment failure are common. Rifampicin, a first-line anti-TB medicine, is given orally for 6-24 months, and only a small fraction of the dose goes to the lungs (the commonest infection site). Direct delivery of rifampicin to the lungs by inhaler could achieve high drug levels in the lungs and blood to treat tuberculosis more effectively. Inhaled rifampicin combined with standard oral dose rifampicin could offer more effective and shorter treatment of tuberculosis, and could reduce side effects and treatment failure. In this project we will use rifampicin in a dry powder inhaler and conduct a clinical study in healthy human participants to confirm safety and determine the optimal dose. This will enable future clinical studies in patients with tuberculosis.

Professor Richard Gearry, University of Otago, Christchurch

Novel biomarker validation to guide treatment in inflammatory bowel disease

36 months, $1,199,994.38

Inflammatory bowel disease (Crohn’s disease and ulcerative colitis) are common in New Zealand. There is no cure and young people live with severe gut symptoms such as pain, diarrhoea, weight loss and bleeding. The treatments include powerful and expensive drugs and major surgery, including stoma formation. At present, there are expected to be in excess of 20,000 New Zealanders living with IBD. These people see specialists often, may be hospitalised and have reduced opportunities in education and employment. We have developed a new test that can accurately determine how inflamed the bowel is. This means that doctors can advise the right treatment for the right patient without them requiring a colonoscopy, which is invasive, expensive and resource-limited in the current health care system. We plan to see how the new test responds to drug therapy. Once this validation has occurred, we will develop a point of care test.

Dr Jemma Geoghegan, University of Otago

Genomic epidemiology of human respiratory viruses in Aotearoa

36 months, $1,196,858.43

New Zealand’s interventions to control COVID-19 have eliminated respiratory viruses that ordinarily circulate annually. An essentially immunologically-naïve population, New Zealand will likely experience larger, unseasonal, and more severe outbreaks in future – like the 2021 Respiratory syncytial virus (RSV) outbreak following borders being opened briefly to Australia. As New Zealand reconnects internationally through quarantine-free travel, we will have a unique opportunity to understand how respiratory infections re-enter and become re-established – generating a complete picture of their spread in New Zealand. To do so we will generate whole viral genomes from patient samples diagnosed with respiratory infections such as RSV and influenza viruses; and extend our genomics-informed surveillance to undiagnosed respiratory infections using a meta-transcriptomics approach. Our world-leading team of infectious disease experts will collaborate to enhance pathogen surveillance and diagnostics in New Zealand and build a genomic pathogen framework, augmenting our ability to respond to future disease outbreaks.

Professor David Grattan, University of Otago

Hormone-induced adaptations in respiratory function during pregnancy

36 months, $1,199,969.09

This proposal aims to reveal the neuronal mechanism controlling maternal respiration during pregnancy. For a healthy pregnancy and to provide sufficient oxygen for offspring development, hormones drive adaptive changes in maternal breathing patterns. Breathing is regulated by serotonin neurons in the brainstem, and we recently discovered that these Report created: 16 June 2022 11:21 Page 3 of 11 neurons express receptors for the pregnancy hormone, prolactin. We hypothesise that prolactin acts to modify the activity of these serotonin neurons in pregnancy to induce adaptive changes in breathing. To test this hypothesis, we will use innovative in vivo radio-telemetry and fibre-photometry techniques to simultaneously measure breathing and neuronal activity in conscious, undisturbed mice throughout pregnancy, and conditional knockout methods to assess the role of prolactin. This unique combination of techniques will represent the first longitudinal study to examine the factors influencing maternal breathing changes, and advance understanding of common pregnancy-associated breathing disorders, such as shortness of breath and sleep apnea.

Professor Parry Guilford, University of Otago

A single-cell transcriptomic approach to gastric cancer heterogeneity

36 months, $1,199,413.46

Cancer cells within single tumours are not all the same. Consequently, drug therapies often fail to kill the entire cancer, leading to rapid relapse. Recently it has become possible to determine the gene expression patterns of thousands of individual cells within a tumour, enabling the heterogeneity within tumours to be observed. We will use single cell RNA sequencing to characterise the cellular heterogeneity within a mouse model of diffuse-type gastric cancer, before and after treatment with a panel of promising drugs. This data will be used to select drugs or drug combinations which can stop the growth of all sub-populations, not just the dominant one. Preferred drugs, and surrogate cellular markers of drug efficacy, will be validated in a novel human ex-vivo stomach model of hereditary diffuse gastric cancer prior to later clinical trials.

Associate Professor Keith Ireton, University of Otago

Role of polarized exocyosis in infection of host cells by pathogenic E. coli

36 months, $1,199,984.57

Enteropathogenic Escherichia coli (EPEC) and enterohaemorrhagic E. coli (EHEC) are important causes of diarrhoeal disease and hemolytic uremic syndrome in NZ and worldwide. These bacterial pathogens stimulate the formation of protrusive structures called ‘pedestals’ that promote colonization of the apical surface of the intestinal epithelium. We hypothesize that pedestal formation involves bacterial exploitation of the host process of ‘polarized exocytosis’, which expands specific sites in the plasma membrane of the human cell. We further propose that EPEC and EHEC stimulate exocytosis by targeting a multi-protein host complex called the ‘exocyst’. We will use genetic, biochemical, and microscopy[1]based approaches to determine if the formation of pedestals involves bacterial subversion of the exocyst, identify microbial factors that elicit exocytosis, and elucidate how exocytosis promotes bacterial infection. We will also use a mouse model system to confirm that EPEC and EHEC induce polarized exocytosis in vivo.

Professor Roslyn Kemp, University of Otago

Immune cells, bacteria and epithelium in Crohn’s disease patients

36 months, $1,190,405.53

~15 000 people in New Zealand are diagnosed with Crohn’s disease (CD), a chronic inflammatory disease that mainly affects the gut. Therapies are poorly targeted to individuals, often resulting in temporary benefits – up to 2/3 of patients become unresponsive to treatment. CD is a heterogeneous disease that involves an interplay of the immune response, the environmental impact on the intestinal epithelial barrier, and the host microbiome, all on the background of genetic susceptibility. The mechanisms and cause of disease pathology, course of disease and efficacy of therapies all vary between individuals. Our overall aim is to determine the drivers of inflammation in onset and maintenance of CD pathology. We have developed a unique intestinal organoid model to simultaneously study the epithelilal integrity, immune response and microbes from individual patients. This work will allow us to identify each contributing factor on a per-patient basis, allowing for targeted therapy.

Dr Sharon Ladyman, University of Otago

Activity of orexigenic AgRP neurons during pregnancy and lactation

48 months, $1,197,681.24

Expecting mothers need to increase food intake to meet the energy demands of the growing fetus, and to store energy as fat in preparation for lactation. The concept of “eating for two” is commonly accepted, but we have little understanding of what drives this increased appetite. It requires adaptive changes in the mother’s brain to overcome the normal regulatory systems that control appetite. In the current environment, such changes make women more susceptible to excessive weight gain during pregnancy, which can have long-term health risks for mother and baby. Neurons expressing AgRP in the hypothalamus region of the brain are recognised as the critical neurons driving food intake. Here we propose state-of-the[1]art techniques to monitor AgRP neuronal activity in conscious females throughout pregnancy and lactation. Our aim is to understand how this important appetite-regulating neuron population adapts to increase food intake during pregnancy.

Dr Rebecca McLean, University of Otago

Whiria te tāngata: Out-of-home mobility of Māori and non-Māori over 65 (NZPATHS)

36 months, $1,198,285.40

Stopping driving can result in depression, declining health, and social isolation. Transitions to driving cessation and alternative transport can be difficult for older drivers and whānau/families. With an ageing population, these challenges and their impacts need to be well understood so they can be adequately addressed. This study has two parts. First, we will continue following older adults (now age 71y+) and family (interviewed in 2016-17, 2019, 2021) to understand how and why older adults modify their driving, how they manage transport needs, effects of transport changes on their health and wellbeing, and the roles families play (NZPATHS). Second, we will recruit and conduct face-to-face interviews with Māori kaumātua (60y+) and whānau to gain a better understanding of their unique experiences and needs (Whānau Study). Findings will contribute to community and national programmes and policy that improve wellbeing, a need identified by Road Safety, Positive Ageing and Wellbeing Strategies.

Professor Alexander McLellan, University of Otago

A dual safety system to promote CAR T cell activation and migration

36 months, $1,199,975.45

Chimeric antigen receptor (CAR) T cell therapy involves treatment of cancer with genetically-engineered immune cells. However successful CAR T cell therapy of solid cancers is limited by migration and activation of CAR T cells at the tumour site. We will use an dual-safety system to improve CAR T cell function and to localise T cell cytokines directly to the tumour site to enhance cell migration and activation. These original approaches will greatly improve the utility of CAR T cells for the treatment of solid cancers.

Dr Matthew McNeil, University of Otago

Targeting metabolic dysregulation to eradicate drug resistant M. tuberculosis

36 months, $1,199,544.36

Antimicrobial resistance is a global health crisis. Drug-resistant strains of Mycobacterium tuberculosis, the causative agent of tuberculosis, are extremely difficult to treat, with long treatment regimens (9-20 months) and low cure rates (2-50%). Antibiotic killing is intrinsically linked to bacterial metabolism, whilst antibiotic resistance in M. tuberculosis is predominantly a result of mutations in antibiotic targets or pro-drug activators that have crucial roles in metabolism, DNA replication, transcription and translation. Here, we hypothesise that primary drug resistance dysregulates mycobacterial metabolism and (I) increases susceptibility to killing by and (II) restricts the evolution of drug resistance against antibiotics that are able to exploit this dysregulation. Using a combination of microbiological, metabolomic and in vivo studies we will reveal and then exploit these metabolic perturbations in drug-resistant strains to identify an entirely new suite of treatment strategies that increase antibiotic efficacy, reduce treatment times and prevent the emergence of drug resistance

Dr Rory Miller, University of Otago

Evaluating a bedside high-sensitivity troponin within a rural chest pain pathway

36 months, $1,199,642.01

Currently patients that present to most rural health facilities do not have access to the same highly precise and sensitive blood tests used to investigate chest pain suspected to be from a cardiac cause. Although current technology is safe for low[1]risk patients, a clinical assessment pathway using a novel high-sensitivity point-of-care troponin test will speed this process and allow rapid identification of low-risk patients allowing investigations to safely occur in the patient’s community in rural general practice, urgent care and rural hospital settings removing existing challenges to implementation. We propose to evaluate this new pathway with mixed-methods that will include measuring the length of stay at health facilities compared with current practice, safety, reduction in transfers and new heart attacks diagnosed that were previously missed; undertake qualitative assessment of the implementation process; an economic cost minimisation study and derive a new risk assessment tool using data obtained throughout this study.

Associate Professor Garry Nixon, University of Otago

Understanding the impact of rurality on health outcomes and healthcare delivery

36 months, $1,199,916.05

Aotearoa/New Zealand has undertaken much less research into the health status of its rural communities than have comparable countries. A barrier to this has been the absence of an agreed definition of ‘rural’. An urban-rural classification system for health has recently been developed and is now available in New Zealand. This project will use this classification along with routinely collected Ministry of Health data to review urban-rural differences in health outcomes. In particular it will examine the interacting impacts of rurality, ethnicity and socioeconomic deprivation on a range health outcomes and utilisation of a range of health services; how people move between urban and rural areas in the later years of life, especially Māori; and the overall per capita cost of providing publicly funded healthcare to rural and the urban areas. The goal is high quality, efficient and equitable healthcare for rural NZers.

Professor Stephen Robertson, University of Otago

Bringing precision to the diagnosis of complex neurodevelopmental disorders

36 months, $1,199,831.41

Neurodevelopmental disorders affect 3-5% of children but frequently management options are limited by diagnostic imprecision. Often genetic factors are important in their cause but an understanding of which genetic factors contribute to causation is lacking. The condition that we will study for this project is termed periventricular nodular heterotopia, a disorder in which neurons become misdirected in terms of their position in the brain during development. In this project we will use combinations of genome sequencing and cellular studies in induced pluripotent stem cells that have been obtained from patients with these conditions to understand the functional effects of these complex genetic underpinnings for these conditions. In particular we will study newly identified neuronal-specific properties of proteins, in particular our new observation that in neurons some genes adopt new functions exclusive to that cell subtype. Our aim is to bring diagnostic precision to families with neurodevelopmental disorders generally.

Associate Professor Logan Walker, University of Otago, Christchurch

Improving genetic health through RNA diagnostics

36 months, $1,190,889.97

The development of next-generation sequencing technologies over the past decade has revolutionised genetic testing of high-risk cancer patients in a diagnostic setting. New sequencing technologies offer increasingly affordable and more powerful approaches for obtaining detailed genetic information. In genomic medicine, this information is used to direct clinical care of patients and their whānau and has significant implications for disease prevention and treatment. While genomic technologies offer great potential to transform clinical care, interpreting the test results is a major challenge for health care professionals. Our proposal aims to address this challenge by developing methods for applying evidence from laboratory assays to determine the clinical significance of DNA sequence variants. Results from this study will have both national and international significance through our various roles in international expert panels that are tasked with improving diagnostic guidelines for clinical and research labs around the world.

Māori Health Project recipient:

Dr Paula King, University of Otago, Wellington

TIAKI – Community wellbeing for whānau with lived experience of incarceration

36 months, $1,199,536.26

As experienced by Indigenous peoples globally, Māori experience unjust mass incarceration, impacting on the health and wellbeing of not only those who are incarcerated but their whanau and communities. Community re-entry is an important opportunity to address the adverse impacts of incarceration on individuals and whānau and will be an important part of the transition away from the system of mass incarceration. Our Kaupapa Māori mixed-methods research addresses contemporary challenges in an area of critical health and justice need for Māori, responding to the vision of a society that prevents harm, addresses its causes, and promotes wellbeing. ‘TIAKI’ focuses on community re-entry wellbeing. We will use routinely collected Government data to understand community entry pathways for Māori and the factors which influence wellbeing outcomes after release. We will support whānau with lived experience of incarceration as researchers to develop strategies for self-determined pathways supporting positive community re-entry wellbeing.

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