HMRI 2010/2011 Project Grant Recipients

Nov 4 2010

HMRI distributed more than $520,000 from community funding at the 2010 HMRI Awards Night, supporting 16 research pilot project grants, four Research Higher Degree Support Grants, and seven Awards and Prizes to individual researchers.

The successful projects grant recipients are below.

HMRI Project Grant

Associate Professor Eugene Nalivaiko and Dr Lisa Lincz
How chronic psychological distress leads to premature aging

The stress response provides the strength and speed to flee from an impending threat. But when it persists, chronic stress increases the risk of obesity, heart disease, cancer, and a variety of other illnesses generally associated with old age.

In vitro studies have recently shown that the stress hormone, cortisol, can affect cellular levels of telomerase, the enzyme responsible for maintaining a cell’s ability to divide and regenerate. This may be the previously missing link between stress and cellular aging.

This study will test this hypothesis of both acute and chronic stress to provide an explanation of stress-induced premature cellular aging, by revealing signalling pathways linking chronic psychological distress to the reduced activity of telomerase.

Such knowledge could lead to more efficient means of preventing age-related diseases and possibly to further expand life expectancy.
Stroud Rodeo and HMRI Project Grant

Dr Rohan Walker and Professor Trevor Day
Establishing the effectiveness of anti-neuroinflammatory agents in the fight against depression

Depression is the leading cause of non-fatal disease burden in Australia.

This group of researchers from the Brain and Mental Health Program has, for the first time, shown that a drug that reduces inflammation in the brain also reduces depression-like symptoms. This project aims to extend upon these extremely promising findings, in the hope of developing a new and more effective generation of antidepressants.

The project will establish the appropriate dose of anti-inflammatory agents in an animal model, that will inform future clinical trials in humans.
Eric and Ann Bone and HMRI Project Grant

Dr Phillip Jobling and Dr Brett Graham
How do the immune and nervous systems interact in arthritis?

The major symptom of rheumatoid arthritis is severe pain. Pain arises from a class of sensory nerve cells known as “nociceptors” which, in arthritic patients become hyper-excitable.

Joint movement that would normally go unnoticed, becomes painful. It significantly limits movement, and substances released from the endings of hyper-excitable nerve cells exacerbate inflammation and joint damage.

The mechanisms underlying this are only just beginning to be resolved. Recently attention has been focused on a range of chemicals released from immune cells. In fact drugs that target one of these chemicals (TNFά) offer some relief to arthritis sufferers. However it is not known where these therapeutic agents act. This study will investigate the distribution of receptors for TNFά on nociceptors in our experimental model of rheumatoid arthritis.

This information will facilitate future development of targeted drug therapy.
Imagine a Life Without Illness Exhibition and HMRI Project Grant

Dr Chen Chen Jiang and Associate Professor Xu Dong Zhang
Regulation of BimS splicing in response of human melanoma cells to inhibition of BRAFV600E

Activating mutation BRAF is found in about 50 per cent of melanomas, which plays a critical role in melanoma cell survival and growth.

Clinical studies with BRAFV600E inhibitors have been very encouraging. Induction of programmed cell death by BRAFV600E-specific inhibitor PLX4720 is associated with preferential induction of BimS, the most potent apoptosis inducer of the three major isoforms of Bim that are generated by alternative splicing.

This project will test the hypothesis that inhibition of BRAFV600E may impinge on one or more splicing factors that regulates BimS splicing. This will provide information on how to regulate apoptosis (cell death) induced PLX4720. Results from this study will provide novel insights into the resistance mechanisms of BRAFV600E melanomas to apoptosis and point to new procedures to sensitise melanomas to mutant BRAF inhibitors.
Lions Club of Adamstown and HMRI Project Grant

Dr Nicole Verrills and Dr Kyu-Tae Kim and Dr Anoop Enjeti
Targeting PP2A as a Novel Therapeutic Strategy for mutant FLT3+ Acute Myeloid Leukaemia

Recent advancements in medical research have led to remarkable improvements in outcomes for some types of leukaemia patients, however survival for patients with acute myeloid leukaemia (AML) remains poor, at a dismal 5-15 per cent for patients over 60 years of age.

To improve the outcome for AML patients, novel therapies are required. This study will investigate the role of a new compound using leukaemia cells from Acute Myeloid Leukaemia patients, with the ultimate goal of moving these new compounds into clinical trials.
HMRI Singleton Foundation Grant

Associate Professor Derek Laver and Associate Professor Dirk van Helden
RyR2 inhibitors as therapy for Ischemia/Reperfusion induced arrhythmias

The mechanisms that trigger fatal cardiac arrhythmias are poorly understood and current treatments are largely ineffective. The design of new and more effective anti-arrhythmic drugs is hampered by the lack of an understanding how an ideal drug should work.

The researchers have recently discovered that flecainide suppressed arrhythmias, associated with a rare inherited disorder Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT), is associated with blocking of Ca2+ release channels in Ca2+ stores of cardiac cells. They hypothesise that this might serve as a therapy for more common arrhythmias caused by overfilling of the Ca2+ stores.

This study will test this possibility by determining if blockade of Ca2+ release channels by flecainide will stabilise arrhythmogenic Ca2+ release caused by transient oxygen deprivation of the heart (ischemia/reperfusion injury).

It is hoped that the results of this research project will provide a detailed understanding of an effective anti-arrhythmic drug strategy; and be a foundation for the design of drugs to control ventricular arrhythmias in coronary artery disease.
HMRI Foundation Chairman’s Grant

Professor Eileen McLaughlin and Dr Brett Nixon
SLX4 – a key regulator of male germ cell development and DNA repair

In Australia, one in twenty males are infertile, with most men displaying aberrant sperm production linked to increased rates of failed fertilisation.

A newly discovered protein SLX4 has an essential role in male germ cell development and the absence of this can result in dysfunctional spermatogenesis and abnormal chromosome numbers. SLX4 is of fundamental interest as a key regulator of sperm quality and malfunction and is implicated in human fertility, miscarriage and cancer.

This project will investigate the role of SLX4 in the regulation of male germ cell development and also the role of this protein in increased susceptibility to cancer.
The Lawrie Bequest Paediatric Oncology Research Grant

Dr Nicole Verrills and Dr Anthony Don
Preclinical testing of PP2A activating compounds for the treatment of childhood acute lymphoblastic leukaemia

This project will show for the first time, the potential of a new class of compounds for improving the survival of childhood acute lymphoblastic leukaemia (ALL) patients. ALL is the most common cancer afflicting children between 1 and 15 years. Current treatment takes around two years, and even after treatment, around one third of ALL patients will relapse, and 20 per cent of children will not survive. The major cause of relapse is due to resistance to chemotherapy.

A new class of drugs were discovered by these researchers. PP2A activating compounds potently inhibit the growth and survival of ALL cells that are sensitive or resistant to current chemotherapy, suggesting that activating PP2A is a potential therapeutic strategy for ALL patients.

This grant will allow them to test the efficacy of these compounds in a clinically relevant animal model of the disease – the necessary next step before they can be tested in human trials.
Rotary Club of Newcastle Enterprise Children’s Research Grant

Dr Jay Horvat and Dr Lisa Wood
Antioxidant therapies for suppressing infection-induced asthma in children

Asthma is most common in children and the majority of adult asthma originates in childhood indicating that asthma is initiated in early-life. Importantly, there are no effective interventions that are widely employed to prevent the development of asthma. This research group has shown that lung infections in newborn and infant, but not adult, mice substantially increase the severity of asthma in later-life. This severe asthma is associated with dramatic changes in lung structure that correlates with evidence of oxidative stress.

Infection-induced oxidative stress and the associated inflammation and damage in the lung in early-life may play an important role in the development of asthma. This study will help determine for the first time if antioxidants can be used to treat oxidative stress and inflammation during childhood infections and reduce the severity of subsequent asthma.

This may lead to the development of novel therapies for the prevention and treatment of infection-induced asthma in children.
Markey Insurance Charity Golf Day Breast Cancer Research Grant

Dr Kathryn Skelding, Dr Nicole Verrills and Professor John Rostas
Regulation of breast cancer growth by a novel phosphorylation-dependent targeting mechanism

Despite improvements in treatments, advanced cancer is generally incurable. New therapeutic strategies that control cancer cell growth are urgently needed.

This project will investigate an exciting and previously unidentified mechanism for controlling the growth of breast cancer cells.

The researchers will identify how to block the growth of new cells, and examine the pathways involved in order to develop new targets for anti-cancer therapies.
Pink Frangipani Ball Breast Cancer Research Grant

Dr Kelly Avery-Kiejda, Professor Rodney Scott and Professor John Forbes
p53 isoforms, a prognostic indicator in breast cancer?

Breast cancer is the most common cancer in women. Estrogen and a gene known to suppress cancer development (p53) are essential for the normal growth of the breast. p53 can control estrogen responses and loss of this control is associated with poor outcome in breast cancer.

Loss of p53 function by genetic fault occurs in far less breast cancers (25 per cent) than expected, given its essential role in stopping cancer growth.

his suggests that its function becomes disrupted in other ways that promote breast cancer. Smaller forms of p53 have been discovered that can inhibit its function. This study will investigate whether small forms of p53 can inhibit the control of estrogen responses by p53, in turn, promoting breast cancer.

This will provide new insights into how p53 loses its function in breast cancer and may identify new targets for its treatment and prevention.
The Dalara Foundation Stroke Research Grant

Prof John Rostas, Dr Neill Spratt, Dr Kathryn Skelding and Sarah McCann
Role of CaMKII Targeting in Stroke Susceptibility and Outcome

The project will investigate the molecular mechanisms by which changes in the signalling protein CaMKII (Ca2+-calmodulin stimulated protein kinase II) can lead to enhanced sensitivity of brain tissue to stroke-induced brain cell death. Recent research indicates that CaMKII activity is a major determinant of brain cell death after stroke. A critical target of CaMKII may be part of the receptor for the main excitatory chemical in brain, known as the glutamate receptor type I (GluR1).  This research has recently identified two potential targeting pathways by which CaMKII may regulate GluR1 through a process known as phosphorylation.

This project will determine the relative importance of the two targeting pathways in determining stroke susceptibility of brain. These pathways could allow selective targeting of CaMKII and lead to new treatments for stroke.
Thomson Family Healthy Lifestyle Research Grant

Dr Suzanne Snodgrass, Professor Clare Collins, Carole James, Dr Ashley Kable, Maya Guest, Samantha Ashby, Professor Ron Plotnikoff and Dr Patrick McElduff
Adult Lifestyle Incentives for Vitality and Energy (ALIVE): Supporting health professionals to assist clients with weight management through lifestyle changes

Obesity is a growing problem throughout Australia. This research will develop and implement a training package to assist regional health professionals to provide healthy lifestyle advice to patients who are overweight or obese. This training will be evaluated by auditing the healthy lifestyle interventions provided by health professionals on an orthopaedic ward in a regional hospital.

The researchers hypothesise that health professionals will provide evidence-based assessment and advice to assist clients with weight management after receiving training, and referrals to weight management services will increase.

his feasibility study will provide data to support a larger grant to expand this initiative across Hunter New England Health, supporting health professionals to provide healthy lifestyle advice to patients.

This will have a significant impact on obesity levels by providing an impetus for regional health professionals to assist patients to follow the evidence-based healthy Lifescripts© messages and make positive changes in their lifestyle habits.
Dr Stephen Graves Multiple Sclerosis Research Project Grant

Dr Jeannette Lechner-Scott and Professor Rodney Scott
MicroRNA in Multiple Sclerosis

This project will investigate miRNA expression in post-mortem brain tissues from subjects with Multiple Sclerosis (MS) and controls, and examine the biological function of miRNAs altered in MS. These small molecules are thought to have a profound influence on the function of genes and may play an important role in the pathophysiology of MS. Significantly, the miRNA molecules may also be novel targets for drug development and/or act as important biomarkers of the disease that can be used in diagnosis and staging of the disease.
 Gallerie Fine Jewellery Cancer Research Grant

Dr Nikola Bowden, Dr Katie Ashton, Dr Stephen Braye, Professor Rodney Scott and Dr Ricardo Vilain
Nucleotide excision repair gene expression in melanoma

Melanoma incidence rates in Australia are amongst the highest in the world. The main cause of melanoma is exposure to UV-light, however, the biological mechanisms involved are not well understood. Cisplatin is a chemotherapeutic DNA-damaging agent used in the treatment of many cancers, however, its effectiveness in melanoma is limited. The removal and repair of DNA damage caused by UV-light and cisplatin, is performed by the nucleotide excision repair (NER) pathway. Our research group reported reduced levels of NER after cisplatin treatment in melanoma cell lines.

The aims of this study are to further examine NER gene expression in melanoma tissue and to investigate the relationship with clinical characteristics.

The outcomes of this project will lead to greater knowledge of the biological pathways involved in melanoma development as a result of UV-light exposure and on the limited effectiveness of cisplatin treatment.
Sparke Helmore / NBN Television Triathlon Festival Depression Research Grant

Dr Carmel Loughland and Dr Linda Campbell
Here’s looking at you, kid: Face processing, emotional availability and reflective functioning in mothers with postnatal depression

Postnatal depression is a debilitating disorder that impacts on the mother, the infant and the broader family.

Understanding how postnatal depression disrupts normal ability to attend to non-vocal cues (emotional displays) in the infant is important for developing therapeutic interventions that target intergenerational transmission of neglect, abuse and mental health disorders in children of mothers with postnatal depression. Interventions are required to improve the mother-baby attachment so as to minimise the cumulative risk factors of unfavourable developmental outcomes for children of mothers with postnatal depression.

This project will investigate the visual responses of mothers to their infants. It is hoped it will led to a diagnostic test to detect mothers at risk of postnatal depression.
The Greaves Family Research Higher Degree Support Grant

Awarded to Megan Jensen
Supervisors: Dr Lisa Wood, Professor Peter Gibson and Professor Clare Collins
Paediatric Obesity, Inflammation & Asthma

Obesity is a significant and increasing health issue for Australian children, with almost one in four Australian youths aged 2-16yrs being overweight or obese. Obesity is characterised by a chronic increase in systemic inflammation, which is likely to be contributing to the development of a range of inflammatory-based diseases, such as cardiovascular disease, diabetes and asthma.

The prevalence of overweight and obesity is higher in children with asthma, which increases their risk of cardiovascular disease. This study will explore the role of disturbed sleep in the development of obesity and increased cardiovascular disease risk in asthmatic children.

Children with asthma experience more sleep disruption than children without asthma, with one in five asthmatic children reporting poor sleep. Sleep disturbance has been linked to an increase in risk factors for obesity, such as an increased consumption of foods high in fat and sugar and reduced physical activity.

This study will characterise sleep patterns in children with asthma using overnight sleep studies and relate these patterns to risk factors for cardiovascular disease and weight gain, including changes in appetite control hormones, physical activity and resting energy expenditure.
The Greaves Family Research Higher Degree Support Grant

Awarded to Todd Jolly
Supervisors: Dr Frini Karayanidis and Associate Professor Mark Parsons

Relationship between white matter legions and cognitive and motor functioning inpatients with minor ischaemic stroke; a structural and functional brain imaging study

Dementia is increasing as our population ages. Today, one in four people over the age of 85 are affected and an estimated 257,000 Australians have dementia. That number is expected to double by 2030 and without a significant breakthrough could soar to almost 1 million by 2050.

Cerebral white matter is especially vulnerable to damage from injuries causing a lack of oxygen to the brain (hypoxic-ischemic injury). Although white matter lesions (WML) in the brain increase with age and underpin vascular dementia, their underlying cause is unknown.

Recently, this research group identified a new magnetic resonance imaging measure that quantifies intracranial pulse waves which may damage the brain’s white matter. This effect known as “pulse wave encephalopathy” may contribute to WML development. WML are associated with a decline in executive functions of the brain in otherwise intact individuals. We have developed targeted paradigms to measure executive function.

This project will examine the effect of our novel “pulse wave encephalopathy” measure, as well as the location and extent of WML on executive functioning. It will use measures that examine patterns of brain activation associated with components of executive functioning integrity. This work has long-term implications for reducing or reversing WML effects on executive functioning in older persons. This in turn will reduce the risk of dementia, prolong functional independence and improve quality of life.
NewcastleInnovation Research Higher Degree Support Grant in Medical Innovation

Awarded to Michelle Wong
Supervisors: Professor Rodney Scott, Dr Nikola Bowden and Dr Kelly Avery-Kiejda

Genetic Variation in Breast Cancer

Breast cancer is the most common form of cancer in women. Breast cancer with familial links has been attributed to inherited abnormalities in the BRCA1 and BRCA2 tumour suppressor genes. However, the familial form of breast cancer only accounts for about five per cent of breast cancer cases worldwide, while the cause of breast cancer in the remaining 95 per cent of cases is unknown.

This research program aims to dive deeper into the genetic causes of inherited breast cancer as well as inherited changes in the function of these genes that could occur even without changes to the genetic makeup of a person with the disease.

Studies into the genetic differences that arise in patients with breast cancer could aid in creating more genetically-personalised treatments for breast cancer patients. It may also offer genetic testing for inheritance of abnormal genes other than the genes already known to be associated with breast cancer. This will be important in the event that a separate inherited component is discovered in the future.

NewcastleInnovation Research Higher Degree Support Grant in Medical Innovation

Awarded to Amanda Smith
Supervisors: Dr Nikki Verrills and Professor Leonie Ashman

Investing the mechanism of oncogenic c-KIT mediated inactivation of the tumour suppressor Protein Phosphatase 2A (PP2A)

Leukaemia is a cancer of the white blood cells that can develop in anyone, at any age, often developing with little warning, requiring immediate and intensive treatment.

Leukaemia is the most common cancer in children aged 0-14 accounting for 38 per cent of child cancer diagnosis. Acute myeloid leukaemia (AML) arises in immature white blood stem cells, myeloblasts, and develops quickly requiring urgent treatment.

In spite of recent developments in leukaemia therapy, the majority of AML patients will die of their disease as the 5 year survival rate is only 13%. Hence understanding the molecular mechanisms that lead to disease is imperative in developing novel, more effective therapeutics.

Mutations in a protein on the surface of AML cells, c-KIT, has been implicated as one cause of a subset of AML cases. Importantly several of these mutations confer resistance to current therapeutics, such as Imatinib. Hence, investigation of other components that are controlled by c-KIT is required to develop novel therapeutics targeted against these cellular pathway components.

Protein Phosphatase 2A (PP2A) is one such component which has recently been recognised as a tumour suppressor (gene/protein that is inhibited in cancer). Amanda’s PhD project has shown the importance of PP2A inhibition by mutant c-KIT in AML and importantly has shown that it can specifically activate PP2A using a novel class of drugs including FTY720.

These drugs inhibit the growth of the AML cells in laboratory models. Targeting PP2A represents a novel approach for the treatment of leukaemias resistant to current drugs. The aim is to determine how PP2A is inhibited by c-KIT and determine how FTY720 activates PP2A and specifically kills the AML cells. This information will provide the basis for improved drug design and ultimately lead to clinical trials of these drugs in AML patients.
Hunter Children’s Research Foundation Grants

These awards were presented at the HCRF Care Awards Dinner on 28 October, 2010.
Carmel Smart, Professor Clare Collins, Dr Bruce King, Dr Patrick McElduff

How do high protein and/or high fat meals affect postprandial glycaemic control in children and adolescents using intensive insulin therapy?

A child or adolescent with Type 1 diabetes is committed to life-long insulin injections, daily blood glucose monitoring and dietary control. Dietary education needs to be clear and evidence based to minimise the burden diabetes places on families, whilst optimising blood glucose levels after meals.

This study will examine the effect of high protein and high fat meals on glycaemic control in children and adolescents using intensive insulin therapy.

here are gaps in the evidence regarding the impact of protein and fat on glycaemic control in children and the appropriate clinical advice to give for high protein and high fat meals.

This new research will have international importance for appropriate dietary education strategies to be used for people with Type 1 diabetes on intensive insulin therapy to optimise glycaemic control and minimise adverse outcomes.

Ms Lorraine Paras, Dr Erica James, Associate Professor Philip Morgan and Dr Marita Lynagh
FamilyFIT: An innovative approach to increasing physical activity for the whole family         

Physical inactivity is a major public health issue. Regular participation in physical activity (PA) benefits children’s cardiovascular, musculoskeletal and metabolic health and reduces the likelihood of overweight and obesity.

A significant proportion of Australian children do not achieve recommended levels of PA. Parents are a major influence on children’s level of PA. There is an urgent need for effective interventions to promote PA across family groups, however little is known regarding effective and sustainable programs that engage parents to promote and role model PA to children.

The aim of this study is to develop and evaluate an innovative family-based intervention to increase children’s PA levels and engage parents to become more active, testing a model that could be widely disseminated across a variety of home and community settings. The unique aspect of the proposed intervention is that it targets both parental and children’s PA and therefore has the potential to establish positive life-long habits and impact both child and parental wellbeing.