Diamantina Health Partners

• National Health and Medical Research Council• Australian Research Council

ResearchGrants 2013

Congratulations to the Princess Alexandra Hospital, Mater, Queensland University of Technology and University of Queensland researchers for being awarded prestigious funding from NHMRC for projects and fellowships commencing in 2013.

Professor Selena BartlettNHMRC Project Grant

Professor Selena Bartlett

The Role of neuronal nicotinic receptor subunits in the self-administration and relapse to alcohol seeking: Treatments for alcohol dependence($513,860 Queensland University of Technology)

Our research project:Alcohol use disorders represent an elusive world-wide problem with few effective treatments. Excessive drinking alone ranks third in leading causes of preventable deaths with a heavy economic burden on society. There remains a need to improve treatment options and strategies to help individuals with alcohol dependence.

Epidemiological studies have shown a high correlation between alcohol consumption and tobacco use. The molecular mechanisms that underpin the co-morbidity of alcohol and nicotine dependence are not well understood. The neuronal nicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated ion channels consisting of different combinations of α2 - α10 and β2 - β4 subunits. Like nicotine, ethanol has been shown to activate neuronal nAChRs. However, unlike nicotine, the subunit composition involved in ethanol’s reinforcing properties remains unknown. The neuronal nicotinic acetylcholine receptors represent pharmacotherapeutic targets for the treatment of alcohol dependence.

The aim of the project is to determine the receptors and brain circuits involved in the effects

of chronic alcohol exposure on the brain.

Potential outcomes of the research:Alcohol dependence impacts millions of individuals and constitutes one of the most serious public health problems worldwide and is a leading risk to health, contributing 4% to the global burden of disease. The estimated economic burden of addiction-related illnesses in Australia exceeds $31.5 billion. The overall goal of my research is to develop pharmacotherapeutics that target the molecular signalling pathways that are induced by high and chronic ethanol exposure but are not altered by social drinking.

Doctor Jyotsna BatraNHMRC Project GrantDr Jyotsna Batra, Professor Judith Clements, Dr Amanda Spurdle

Identification and characterisation of a novel genetic signature at the 5p15 region associated with risk of prostate cancer($590,222 Queensland University of Technology)

Our research project:Prostate cancer is the most common cancer in Caucasian men. However, early detection through screening programs has proven challenging, and about 30% of the 19,000 new cases diagnosed annually in Australia already have advanced disease. Prostate specific antigen (PSA) has proven utility as a biomarker for biochemical recurrence, but controversy surrounds its use diagnostically as it has not been able to discriminate more aggressive from indolent disease leading to significant over treatment issues.

Major breakthroughs have occurred in the last few years in our understanding of the genetics of common diseases, including cancer. Genome wide association studies (GWAS) which assess thousands of single nucleotide polymorphisms (SNPs) in large cohorts have provided new insights into the genomic regions that alter an individual’s risk of developing cancer. These efforts have led to the discovery of multiple common risk variants for several types of diseases including prostate cancer. Studies that have identified potential risk SNPs have repeatedly emphasised the importance of functional studies that need to be followed up with their association study. Biological insights can then be translated to clinical benefits, including reliable biomarkers and effective strategies for screening and disease prevention.

The project aims to undertake the fine mapping and functional studies of the recently identified prostate specific region at 5p15 locus in multi ethnic populations by us and others to determine the causal variant at this locus, for future risk prediction modelling of

the disease.

Potential outcomes of the research:Our study underpins the ongoing development of multigenic SNP models for risk prediction, which are intended, in the long term, to help categorize men into various levels of cancer risk pre-symptomatically, or at least at an early stage of their disease. This assignment could be beneficial in choosing men for surveillance and potentially for chemoprevention. It is also possible that, among men who undergo prostate-specific antigen (PSA) screening, our approach could provide important predictive information beyond that of the PSA levels itself.

Professor Kenneth BeagleyNHMRC Project Grant

Professor Kenneth Beagley, Professor Peter Timms, Professor Richard Blumberg, Dr Danica Hickey

pH-dependent, antibody-mediated enhancement of genital chlamydial infection: implications for vaccine design?($360,431 Queensland University of Technology)

Our research project:Genital tract antibodies are usually believed to provide protection against sexually transmitted infections such as Chlamydia, and vaccines to target these infections aim to elicit high levels of mucosal antibodies in the female and male reproductive tract. Our recent studies, however, have shown that due to the acid pH of the reproductive tract and the expression of a pH-dependent antibody transporter, the neonatal Fc receptor (FcRn) some antibodies in the genital tract may actually enhance infection by promoting uptake of bacteria into the epithelial cells lining the reproductive tract.

In the proposed studies we will look at different types of antibody, produced by either natural infection or vaccination, directed against different chlamydial proteins to define the role of these antibody types in either promoting or protecting against infection. We will also determine if these antibodies contribute to ascending infections, which can lead to pelvic inflammatory disease, infertility and ectopic pregnancy, the most severe outcomes of

Chlamydia trachomatis infection.

Potential outcomes of the research:The studies will allow us to differentiate between antibodies that provide protection against Chlamydia infection and those that may actually enhance infectivity and exacerbate chlamydial disease that can lead to infertility. This information will be essential for the development of effective vaccines to target sexually transmitted infections and prevent disease.

Dr Antje BlumenthalNew Investigator Grant

Dr Antje Blumenthal

A new macrophage sensor for Mycobacterium tuberculosis($506,349 The University of Queensland)

Our research project:Tuberculosis remains one of the major infectious disease threats globally. The lack of an effective vaccine that sufficiently protects adults, as well as the emergence of drug resistant bacteria currently pose challenging tasks and have made the development of improved diagnostics, an effective vaccine and novel treatment options urgent priorities in the global fight against tuberculosis. A key strategy towards achieving these goals is to improve our understanding of the interactions between the bacteria that cause tuberculosis and the host. This entails characterising the determinants of the immune control of this importantpathogen.

This study will characterise the interactions between the bacteria and a newly identified sensor molecule on their host cell, the macrophage. These immune cells are well equipped to destroy pathogens and are amongst the first to initiate immune responses during infection. However, tuberculosis bacteria can evade those killing mechanisms and reside within macrophages. This project will specifically address how the new macrophage sensor molecule recognises tuberculosis bacteria and what molecular interactions are involved in initiating appropriate immune responses aimed to contain the infection.

Potential outcomes of the research:Tuberculosis remains a global health emergency currently causing about 1.4 million deaths worldwide every year. It is estimated that one third of the world’s population is latently infected with tuberculosis bacteria, which poses a lifetime risk of 10% of developing active disease. Immune-compromising conditions, such as HIV co-infection and some therapies for chronic inflammatory diseases, significantly increase the risk of developing tuberculosis.

This project will increase our understanding of how tuberculosis bacteria interact with the host and how this impacts on the immune response and the outcome of the infection. Given the central role of specific immune mediators in the control and pathology of active and latent tuberculosis, such knowledge is essential to understand the immune pathogenesis of the disease and manage the risk of tuberculosis reactivation associated with immune-modulatory treatments. Furthermore, defining specific agonists for macrophage sensors might prove valuable in eliciting selective immune responses in adjuvant strategies for vaccine development.

Vanessa BrunelliNHMRC Postgraduate Scholarship

Vanessa Brunelli

Evaluating a program for developing specialist cancer nurse competencies for effective and sustainable self-management of dyspnoea in lung cancer patients($85, 585 Princess Alexandra Hospital)

Our research project:In Australia, in 2007, lung cancer was the fourth most commonly diagnosed cancer and accounted for the most cancer deaths at a rate nearly 50% higher than all other Australian cancer deaths. Currently, lung cancer represents the highest burden of disease in Australia for its high mortality and its impact is significant. Breathlessness, a common and distressing symptom of lung cancer, adds substantially to the burden. Reports indicate that the majority of people with lung cancer experience breathlessness with the prevalence increasing to nearly 90% in the time period just prior to death, making these people more likely to die in hospital. There is increasing evidence that a range of patient self-management strategies used in conjunction to traditional medical interventions can improve control of breathlessness in patients with lung cancer. This study aims to develop and evaluate a program designed to develop specialist cancer nurse competencies to support lung cancer patients to use effective, sustainable breathlessness self-management strategies. The outcomes of this study will assume a key role in instituting person-centred models of integrated cancer service delivery in adding to the limited knowledge on what skills and abilities are required of nurses to support patient self-management, and how these might best be developed.

Potential outcomes of the research:Breathlessness is a common symptom of lung cancer and adds substantially to the disease burden. Consistent with major initiatives, this study supports a paradigm shift to patient self-management for sustainable cancer service provision. It will assume a key role in instituting person-centred models of integrated cancer service delivery in adding knowledge on what abilities are required of nurses to support patient self-management.information which will lead to more consistent and optimal care for future patients diagnosed with pancreatic cancer.

Elizabeth BurmeisterNHMRC Postgraduate Scholarship

Ms Elizabeth Burmeister

Patterns of care in patients with pancreatic cancer($78, 437 Princess Alexandra Hospital)

Our research project:This project will describe the diagnostic and treatment patterns of patients with pancreatic cancer throughout QLD and NSW and will be the largest and most comprehensive study of the management of patients with pancreatic cancer conducted in Australia. A quality of care score will be developed, and the care of patients in this cohort benchmarked against the score. The impact of patient characteristics on the quality of care provided will be assessed, as will the impact of quality of care on survival.

Potential outcomes of the research:By assessing the impacts of patient and health system characteristics on the “quality of care score” plus assessing the impact of this score on survival this project will provide information which will lead to more consistent and optimal care for future patients diagnosed with pancreatic cancer.

Dr John DuleyNHMRC Postgraduate Scholarship

Dr John Duley, Dr Helen Liley, Professor Paul Shaw, Dr Christine Knox, Associate Professor Bruce Charles

A mechanism for regulation of oral and gut microflora by interaction of salivary metabolites with breast milk ($597,089 University of Queensland)

Our research project:Saliva “lacks the drama of blood, the sincerity of sweat and the emotional appeal of tears”. But spit has important roles for the mouth & digestion. Now researchers in Brisbane have found baby dribble has natural chemicals that form ‘nucleotides’ in the body. They are testing the theory that the nucleotides encourage friendly bacteria in the mouth and gut. When baby saliva mixes with breast milk it also makes natural antibiotics called ‘oxidative radicals’ that stop bad bacteria. Thus, the chemical interaction of baby saliva with breast milk may play a critical role in innate immunity, protecting from mouth & intestinal infections. This research reveals a new mechanism that scientifically shows why ‘Breast is best’. This mechanism may also help to prevent ear infections, which arise from oral/throat bacterial invasion and are less common in breast-fed babies, as well as protecting the mouth and gut from more serious infections. Studying the infants’ oral microflora will help us understand the mechanism of action of milk and saliva on bacteria and their role in regulation of microflora. This will also open a research field for further studies

Potential outcomes of the research:This project unites an experienced team of researchers from pathology, pharmacy, neonatology and microbiology at UQ, QUT and Mater Hospital. By studying this early postnatal mechanism regulating oral and gut microflora, we may improve the oral and gastric health of newborns, especially intensive care babies who are prone to oral infections (e.g. Candida) and life-threatening gastrointestinal diseases (e.g. necrotising enterocolitis, which has 40% mortality).

Dr Liliana Endo-MunozNew Investigator Grant

Dr Liliana Endo-Munoz, Associate Professor Nicholas Saunders

Characterisation of two novel markers of osteosarcoma metastasis as potential therapeutic targets($602,877 The University of Queensland)

Our research project:Osteosarcoma (OS) is the most common bone tumour in children and adolescents. In spite of aggressive chemotherapy, OS tumours that metastasise to the lungs result in dismal long-term survivals of only 10-20%. For these patients, new treatment options are desperately needed.

In this proposal we show compelling data identifying two new markers of OS metastasis. This research aims to validate the suitability of these novel markers as therapeutic targets to prevent OS metastasis. This proposal aims to improve survival of paediatric osteosarcoma patients to ensure they get a chance at healthy ageing. Alternative and focused therapies such as that described in our proposal, also focus on reducing the long-term deleterious effects of multi-agent chemotherapy treatments currently in use for this cancer, ensuring healthier ageing. Although osteosarcoma occurs mainly in children and adolescents, a second peak incidence occurs at age 65 and over. Thus, this proposal also addresses the

treatment and management of cancer in the older population.

Potential outcomes of the research:Osteosarcoma (OS) is the most common malignant primary bone tumour in children and adolescents. Lung metastasis is the most significant and untreatable complication of osteosarcoma. In spite of aggressive chemotherapy, patients who develop metastatic disease have a 5-year survival rate of less than 20%. In order to improve outcomes, these patients will require treatment with novel targeted therapeutics. To do so it is critical to unravel the molecular basis behind the metastatic process and identify novel drivers of metastasis.

Associate Professor Geoffrey FaulknerNHMRC Project Grant / Career Development Fellowship

Associate Professor Geoffrey Faulkner, Dr Ryan Taft

Somatic retrotransposition drives neoplastic mutagenesis in glioblastoma multiforme($643,847 Mater Medical Research Institute)

Our research project:Understanding cancer, and ultimately developing effective targeted therapies, will require that genetic mutation be systematically investigated in all phases of the disease, from pre-neoplasia to overt cancer. It will also require a full catalogue of mutational processes that trigger tumour formation and growth. Retrotransposons are one potentially overlooked mutagen contained within the human genome. These mobile genes copy-and-paste themselves during developmental and later life, causing each cell in the human body to be genetically unique.

In a recent landmark publication in Nature, we demonstrated that retrotransposons move in the healthy human brain. In the current study, we will use cutting-edge genomics technologies to determine whether these mutations affect genes that prevent tumour formation in glioblastoma multiforme. This will also likely reveal a new cohort of genes that are mutated principally by retrotransposons and not other mutations, elucidating novel

candidate genes associated with glioblastoma.

Potential outcomes of the research:There is a clear need to improve upon the current genetic explanation for glioblastoma. It is a particularly devastating disease; the average survival is only 14.6 months for the most common and high-grade lesions and children are disproportionately affected. Treatments poorly control tumour progression and only a small survival increase has been achieved over the past thirty years. This project is therefore ultimately intended to improve treatments that use “personalised medicine” to reduce the public health impact of cancers of the brain and other organs.

Associate Professor Geoffrey FaulknerNHMRC Project Grant

Associate Professor Geoffrey Faulkner, Dr Lucia Clemens-Daxinger, Dr Kyle Upton

Epigenetic regulation of L1 retrotransposition in mouse models of abnormal human neurobiology($403,390 Mater Medical Research Institute)

Our research project:The genetic causes of most neurological diseases remain, on the whole, poorly understood. Here we will use genome-scale approaches to determine how retrotransposons, a class of mobile DNA, change the genetic makeup of neurons in a mouse model of the neurodevelopmental disorder Rett syndrome (RTT). This will address the far-reaching question of whether retrotransposition in neurons modifies their function, i.e. do genetic changes occur during life that may affect how the brain works? It will also address whether too many of these mutations can cause neurodevelopmental syndromes and hinder

restorative treatments based on gene therapy.

Potential outcomes of the research:In studying Rett Syndrome, this project seeks to address the fundamental basis of a severe neurodevelopmental disorder that is characterised by profound developmental regression, impaired mobility and speech. These significant physical and intellectual disabilities result in increased health needs for patients. In Australia, RTT is estimated to affect 1 in 8500 females and, although it is a relatively rare disorder, fully resolving the causes of RTT would assist its treatment and may have major implications for other neurodegenerative or neurodevelopmental conditions.

Professor Ian FrazerAustralian Research Council Grant

Professor Ian Frazer, Professor Mark Kendall

Sterile inflammation as a determinant of adaptive immunity($500,000 The University of Queensland)

Our research project:Inflammation in response to injury is a key component driving the physiological adaptive immune response.

The proposed research aims to understand how tissue damage following injury, as opposed to infection, regulates the immune response to self and non-self antigens presented at the

site of the physical injury.

Potential outcomes of the research:Injuries are common and the resultant inflammation can either help healing, prolong local tissue damage, or lead to autoreactive immune responses.

We understand some part of how the response to non-infectious tissue damage is regulated through the inflammasome (multiprotein oligomer), and wish to establish how variability in the inflammasome response may either protect us from, or alternatively promote, self-damaging immune responses.

Professor Len GrayNHMRC Project Grant

Professor Len Gray, Dr Melinda Martin-Khan, Professor Elizabeth Beattie, Dr Sisira Edirippulige, Associate Professor Trevor Russell, Associate Professor Anthony Smith, Professor Deborah Theodoros, Associate Professor Ian Scott, Doctor Ruth Hubbard

Telehealth in residential aged care facilities: a pragmatic randomised control trial($972,605 The University of Queensland)

Our research project:Residents of aged care facilities have limited access to specialist medical care because they cannot travel alone. We have devised a telehealth solution to enable specialists to “visit” residents through video-conference. Each new resident will undergo assessment with a geriatrician to assist with development of a health plan.

Our study will examine whether this new approach to care has benefits for the resident (improved health and quality of life), the facility (improved quality of care and efficiency) and the system (reduced transfers to hospital, reduced medication use). The trial will involve 10 facilities in Brisbane, half of which will be randomly selected to receive the telehealth system. Comparisons between the outcomes will be made with the 5 control

facilities over the ensuing 6 months.

Potential outcomes of the research:There are 2760 aged care facilities in Australia, admitting 64000 new high care residents per year. For every 100 residents there are between 50 and 100 transfers to emergency departments each year. There is a widespread perception that quality of care can be improved. Our approach is feasible, scalable and affordable. It is essential to demonstrate that it is effective to justify its rollout.

Associate Professor Carmel HawleyNHMRC Project Grant

Associate Professor Carmel Hawley, Associate Professor Grahame Elder, Professor Robert Walker, Dr Geoffrey Block, Professor Randall Faull, Associate Professor Kevan Polkinghorne, Associate Professor Nigel Toussaint, Associate Professor Eugenia Pedagogos

A randomised, double-blind, placebo-controlled trial to assess the effect of phosphate reduction with lanthanum carbonate on arterial compliance and vascular calcification in patients with chronic kidney disease stages 3-4($1,596,697 The University of Queensland)

Our research project:Compared to people with normal kidney function, those affected by chronic kidney disease (CKD) are at high risk of developing cardiovascular disease (CVD). In CKD there is an association between serum phosphate, CVD and death. This trial will investigate the effect of a non-calcium phosphate binder called lanthanum carbonate on lowering phosphate in early CKD over 2 years. The study will examine:1. Functional and structural cardiovascular changes by measuring the stiffness of arteries

and the size and structure of the heart.2. Changes in Bone Mineral Density 3. The levels of FGF-23 (a phosphate regulating hormone) to understand the role of this

hormone in the cardiovascular, bone and hormonal abnormalities.

Potential outcomes of the research:This study will inform clinicians whether early management of phosphate disturbances improves markers of cardiovascular disease in CKD. The project has the potential to develop a treatment to manage mineral and bone disorders in CKD. It will provide data as to the role of the phosphate regulating hormone, FGF-23, in the development of CVD and therefore a promising therapeutic target.

Professor Dietmar HutmacherNHMRC Project Grant

Professor Dietmar Hutmacher, Professor Michael Schuetz, Dr Devakar Epari, Dr Mia Woodruff, Dr Roland Steck, Dr Ian Dickinson, Professor Peter Choong, Dr Simon Pearce, M. Swee-Hin Teoh, Mr James Green, Mr Mike Lehmicke

Bioactive and biodegradable scaffold and novel graft source for the repair of large segmental bone defects ($440,902 Queensland University of Technology)

Our research project:The project demonstrates the efficacy of a novel treatment for regeneration of large volume segmental bone defects, using a preclinical animal model that will provide the preclinical data necessary for planning of future human clinical trials. Large segmental bone defects occur as a result of trauma, deformity correction or removal of diseased and cancerous bone. While the human body is capable of minor bone defect repair, intervention is typically required to regenerate defects greater than 3 cm in length.

The current “gold standard” treatment is limited due to the volume of graft material that can be extracted and the significant pain associated with damage to the donor site. An alternative procedure has been developed which utilises a reaming tool to collect bone debris. Synthes has developed the Reamer-Irrigator-Aspirator (RIA), which enables collection of viable bone tissue during the reaming process with minimal pain at the donor site. The extracted material is sufficient to treat small bone defects, however to successfully repair larger defects the graft must be combined with an artificial scaffold.

The CI team has developed and tested medical grade polycaprolactone tricalcium phosphate (mPCL-TCP) scaffolds, to be used as a carrier for the graft material maintaining the required configuration to fill and regenerate the defect. The scaffold degrades slowly over time and is replaced by native tissue to restore healthy bone. However the use of these components significantly increases the treatment cost. In this project, the CI team will trial a novel strategy for the repair of large bone defects by combining the harvest of bone graft material using the RIA approach followed by its implantation and retention at the defect site within a pre-manufactured mPCL-TCP scaffold, in a single operative procedure.

Potential outcomes of the research:In the longer term, the successful translation of the RIA/mPCL-TCP Scaffold System into clinical practice will provide significant benefits to patients, enabling the repair of major defects which would otherwise require amputation or prosthesis, and providing repair solution for less severe defects which is less invasive, and involves lower morbidity and risk than conventional practices.

Professor David JohnsonNHMRC Project Grant

Professor David Johnson, Professor David Harris, Professor Randall Faull, Dr Suetonia Palmer, Associate Professor Neil Boudville, Dr Sunil Badve, Dr Gopala Rangan, Associate Professor John Kanellis, Professor Robert Walker, Dr Fiona Brown

Controlled trial of slowing of kidney disease progression from the inhibition of Xanthine oxidase (CKD-FIX): A double-blind, randomised, placebo-controlled trial($1,917,146 The University of Queensland)

Our research project:Chronic kidney disease (CKD) affects approximately 1.7 million Australian adults. Current treatments for slowing CKD progression are limited and only partially effective. The CKD-FIX study is an international controlled clinical trial designed to test whether a drug called allopurinol safely and effectively slows loss of kidney function over a 2-year period in 620 patients with moderate-to-severe CKD being treated at hospital centres in Australia, New Zealand, China, Malaysia and other countries. The trial will also look at whether allopurinol lowers blood pressure, reduces protein leakage from the kidneys, reduces heart attacks, improves quality of life and is cost-effective in this important patient group. Demonstration of a significant benefit of allopurinol in CKD patients will provide doctors with an important, new and relatively inexpensive strategy for effectively treating CKD leading to significantly improved health outcomes for CKD patients and potential savings to the Australian health

budget of hundreds of millions of dollars annually.

Potential outcomes of the research:Chronic kidney disease (CKD) is a large and growing public health problem in Australia and worldwide. The proportion of Australian deaths attributed to CKD has increased from 9.5% in 2001 to 13.5% in 2009. Each year in Australia, nearly 1 billion dollars is spent annually on dialysis and kidney transplantation. CKD disproportionately affects indigenous Australians and is the most common cause of hospitalisation in Australia (15% of all hospitalisations).

Associate Professor Jean-Pierre LevesqueNHMRC Project Grant

Associate Professor Jean-Pierre Levesque, Dr Allison Pettit, Dr Ingrid Winkler

How does the bone marrow regulate normal blood formation and leukaemia progression?($590,785 Mater Medical Research Institute)

Our research project:The millions of blood and immune cells we consume every second of our life must be replaced. This is the work of blood stem cells. These very rare stem cells are niched in the bone marrow where they obey instructions given by bone marrow and bone cells. Not enough blood cell produced leads to anaemia, immunodeficiencies or bone marrow failure. Too many cells produced lead to blood cancers. This Senior Research Fellowship will enable A/Prof Levesque to continue his research to better understand how blood cells are formed, how factors from the bone marrow and the bone influence the behaviour of normal blood forming cells (called haematopoietic stem cells), and also influence leukaemia progression and response to chemotherapy treatments.

During his research, he has also discovered that bone, blood, immune and nervous systems cross-talk and influence each other. This opens now horizons to treat poorly understood and to-date untreatable bone pathologies resulting from the deregulated cross-talk between the

immune and nervous systems.

Potential outcomes of the research:Blood cancers affect an increasing proportion of Australians. While enormous progress has been made to treat childhood leukaemias, other forms of leukaemia prevalent in adults still have very poor survival rates. A/Prof Levesque’s research has already improved blood stem cell transplantations used to treat cancer patients. His continuing research will improve the efficacy of chemotherapies to treat leukaemia and discover new methods to reduce the toxicity of chemotherapy treatments to healthy stem cells. These results will lead to increased cure rates and decreased mortality caused by the chemotherapy treatments.

Associate Professor Jean-Pierre LevesqueNHMRC Project Grant

Associate Professor Jean-Pierre Levesque, Dr Allison Pettit, Dr Ingrid Winkler

Do bone marrow macrophages regulate leukaemia stem cells and their response to treatment?($569,737 Mater Medical Research Institute)

Our research project:Acute myeloid leukaemia is very resistant to chemotherapy treatments. This is due to leukaemia stem cells that reside in protective niches in the bone marrow. While the bulk of fast proliferating leukaemia cells are killed by chemotherapy treatments, the leukaemia stem cells resist in their protective niche and will restart the leukaemia once the chemotherapy treatment is stopped. Over time these leukaemia stem cells mutate and make new leukaemia cells that resist treatment altogether. At this stage, the leukaemia can’t be stopped from taking over the patient’s blood and immune system causing death.

This project is to target bone marrow cells that give protection to the leukaemia stem cells. These cells are called macrophages and are the guardians of our body in charge of destroying invaders and clean up tissues to keep them healthy. We have found that leukaemia cells can reprogram macrophages to their advantage. The project is to test whether targeting macrophages in the leukaemic bone marrow will increase the sensitivity

of leukaemia stem cells to chemotherapy treatments and prevent relapse.

Potential outcomes of the research:Acute myeloid leukaemia remains one of the most deadly leukaemia with 850 new cases diagnosed and more than 700 patients dying of the disease every year in Australia. This project is to target cells that protect leukaemia stem cells from chemotherapy treatments in order to kill them more efficiently with chemotherapy and improve the very low cure and survival rates or acute myeloid leukaemia.

Dr Stephen MattarolloNew Investigator Grant

Dr Stephen Mattarollo

Therapeutic vaccine against non-Hodgkin’s lymphoma targeting the immune adjuvant properties of Natural Killer T cells($434,640 The University of Queensland)

Our research project:Patients with lymphoma cancers initially respond well to treatment, but later relapse with disease. The immune system can be effective at controlling cancer. A potential treatment option is to boost the natural immune response against cancer.

This study investigates a vaccine that activates a certain immune cell, NKT cells, to fight lymphomas by delivering an NKT cell-activating molecule. Outcomes will allow assessment

of combining an NKT-based vaccine with established treatments for lymphoma.

Potential outcomes of the research:Cancer is a growing problem in Australia as the population ages. In 2007 cancer accounted for 40,287 deaths or 29% of all deaths registered. Therefore, cancer is a major cause of death and financial burden in Australia. Indolent non-hodgkin’s lymphomas (NHL) are still considered incurable with standard therapy with current 5 year survival around only 62%.

The current proposal addresses the need for new therapeutic options by investigating the therapeutic efficacy of a novel tumor cell-based vaccine which incorporates an immune adjuvant that aims to boost an anti-tumor immune response against NHL. Initially this will be assessed in a pre-clinical mouse model representing NHL with the objective to translate outcomes from this study into a phase I clinical trial in low-grade NHL patients in the near future.

Professor Michael McGuckinNHMRC Project Grant

Professor Michael McGuckin, Dr Sumaira Hasnain, Professor Timothy Florin, Associate Professor David Serisier, Dr Simon Phipps

Understanding the interplay between ER stress and inflammation($541,472 Mater Medical Research Institute)

Our research project:Endoplasmic reticulum or ER stress occurs when proteins fold incorrectly as they are being made inside the cell. ER stress occurs in genetically inherited syndromes where proteins misfold because of mutations, for example in cystic fibrosis. Additionally it is now apparent that ER stress is a feature of many chronic diseases involving inflammation such as arthritis and inflammatory bowel diseases. We have found specific factors made by immune cells that cause ER stress and also other immune factors which block ER stress even in the face of a genetic defect. This opens the way for therapeutic approaches to control ER stress to treat these diseases.

In the funded grant we seek to gain a deep understanding of the immune regulated

pathways controlling ER stress with a view to developing new treatment approaches.

Potential outcomes of the research:Chronic inflammatory diseases affect hundreds of thousands of Australians and consume tens of billions of dollars in the health budget. Rheumatoid arthritis alone affects over 500,000 Australians. Our findings offer a new angle for treating these common diseases, and has the potential to reduce suffering and save costs in the health system. The proposed research will provide proof of principle in model systems that will then need to be tested in clinical trials.

Dr Peter MolleeNHMRC Project Grant

Dr Peter Mollee, Associate Professor Glen Kennedy, Associate Professor David Looke, Ms Rosita Van Kuilenburg

Central venous catheter-associated bloodstream infections in patients with cancer: A prospective randomised controlled trial($86,658 Princess Alexandra Hospital)

Our research project:Central venous access devices are special intravenous lines that enable chemotherapy, blood transfusions, antibiotics, intravenous feeding, painless blood sampling and other supportive therapies to be given to patients with cancer. The main limitation and complication of CVADs is infection in the blood originating from the line causing significant patient illness and even death. These blood-stream infections also contribute to increased costs of health care, primarily through longer hospital stay and greater treatment costs. Any interventions to reduce these infections would be a major clinical advance.

In a recent study at Princess Alexandra Hospital of 1127 CVADs in 727 patients with cancer, we have found that the side of the body that CVADs are inserted significantly affects line-associated infection, with right sided insertions having the highest infection rate. We speculate that this is because most patients are right-handed and the increased movement of the dominant arm increases the risk of infection.

We propose to confirm this finding by performing a prospective randomised controlled trial where patients will have CVADs inserted in their dominant or non-dominant side. The trial will be performed at two centres: the Princess Alexandra Hospital and the Royal Brisbane

and Women’s Hospital.

Potential outcomes of the research:Bloodstream infections are a significant complication of CVADs, affecting a large proportion of patients with cancer. If such a simple intervention as preferentially inserting CVADs in the non-dominant side of the body could reduce infections (by an estimated 60%), it would be a major advance in patient management with reduced morbidity and health economic benefits

Dr Arnold NgEarly Career Fellowship

Dr Arnold Ng

Pathophysiology of diabetic heart disease($179,782 Princess Alexandra Hospital)

Our research project:Diabetic patients often develop weakness of the heart muscle and eventual clinical heart failure. The cause of this heart muscle weakness is multifactorial, ranging from altered cell function, accumulation of fat within heart cells, abnormal microscopic blood vessels and obstruction of the coronary arteries.

The aim of this study is to determine the role of increased fat droplets within the heart cells and subsequent microscopic scarring and altered muscle contractility. This will be

performed using state-of-the-art imaging using MRI and echocardiography (ultrasound).

Potential outcomes of the research:The prevalence of diabetes is increasing world-wide, and up to 60% of diabetic patients have altered heart function, a major cause of morbidity and mortality. Understanding the role of intramyocardial fat accumulation in diabetic patients may shed light on future therapeutics that improves diabetic cardiovascular outcomes.

Associate Professor Andrew PerkinsNHMRC Project Grant

Associate Professor Andrew Perkins, Dr Marcel Dinger

lncRNAs and mesoderm formation($555,112 Mater Medical Research Institute)

Our research project:“It is not birth, marriage, or death, but gastrulation, which is truly the most important time in your life.” This famous quote by Lewis Wolpert (1986) highlights the importance of gastrulation, which describes the process of ingression of cells between the ectoderm and endoderm germ layers early in life. It is an ancient cell movement that generates the precursors of all of our internal organs, and thus it underpins animal evolution from flatworms.

We have discovered that a new type of genetic material, known as long non-coding RNA, which was once considered to be ‘noise’ in the genome, is in fact essential for gastrulation. This grant will determine how one form of lncRNA works, and how it can be harnessed to

generate useful stem cells for treatment of human diseases.

Potential outcomes of the research:This grant proposal has profound implications for our understanding of Darwinian natural selection drivers. It will challenge the long held dogma that proteins made by genes are the drivers of development and evolution. If we can harness the activity of lncRNA master control genes, we have the potential to revolutionize stem cell therapies for degenerative diseases and cancer.

Professor Elizabeth PowellNHMRC Project Grant

Professor Elizabeth Powell, Associate Professor Andrew Clouston, Dr Katharine Irvine, Dr Kelli MacDonald, Dr Matthew Sweet

Defining the role of MMP-9-expressing macrophages in liver injury in chronic liver disease($523,321 The University of Queensland)

Our research project:Defining the pathways that lead to fibrosis in chronic liver disease is an urgent priority and unmet need because cirrhosis remains a major cause of death. We will study the development of an additional fibrogenic pathway involving altered liver repair mechanisms, in order to seek ways to restore liver function.

The goal of this project is to understand the connections between liver repair and regeneration, in particular the relationship between injury, macrophage infiltration, the hepatic progenitor cell and fibrosis. Our study will establish whether macrophage-derived MMP-9 is a key mediator in the progression of fibrosis during ongoing liver injury, and importantly, whether inhibition of MMP-9 can reduce fibrosis without impairing liver regeneration. Since we have already established a clinical association between MMP-9 expression and stage of fibrosis, the outcomes from this project will have immediate translational relevance. Furthermore, a number of therapeutic agents currently being evaluated for inflammation-associated diseases are reported to down-regulate MMP-9 expression, so this project should not only identify mechanisms of disease, but also potential avenues for therapies. This is important because few anti-fibrotic therapies are in clinical trials, and targeted strategies that modify the natural history of progressive fibrosis are urgently required.

Potential outcomes of the research:Our study is important and unique because it addresses the poorly understood connections between innate immunity and fibrosis. New insights arising from this novel research could significantly advance our understanding of how fibrosis develops. It will generate findings that may lead to novel approaches to therapy and improvement in clinical outcome of patients with chronic liver disease

Dr Tarl ProwAustralian Research Council Grant

Dr Tarl Prow, Professor Peter Soyer

Image-guided skin microbiopsy technology development($370,000 The University of Queensland)

Our research project:We have recently developed a novel microbiopsy (0.2 mm) device for skin. In this project, we will develop two visually guided targeting systems that will enable clinical uptake of this technology. The first device will be a hand held, electrically actuated microbiopsy device that is guided by eye that will then be integrated with the dermatoscope, a common dermatology magnification device for looking at skin lesions that employs polarized light.

The development of these devices will enable minimally invasive microbiopsies to be taken from small lesions and even from suspicious areas within lesions without the need for conventional biopsies (4 mm). This is expected to improve disease detection and minimize

the need for conventional biopsies

Potential outcomes of the research:The technology described in this proposal will impact the tens of thousands of people who visit the dermatologist every year motivated by a suspicious skin growth. The success of this Project has the potential to improve clinical diagnosis, but importantly, also the potential to change skin research by enabling researchers to follow the molecular changes in lesions over time.

Professor Michael RobertsNHMRC Project Grant

Professor Michael Roberts, Professor Mark Kendall

Specific targeting of nanosystems by cutaneous delivery($951,201 University of South Australia)

Our research project:The skin is a major site for the delivery of drugs or cosmetics and increasingly, for vaccines and diagnostic substances. However, the skin also forms a very effective barrier to the outside world, which is difficult for most substances to pass through. A key challenge therefore, is to deliver sufficient quantities of these agents to achieve the desired responses.

Our approach uses ‘nanosystems’ to act as delivery vehicles for substances that are difficult to get through the skin, such as very large or very polar molecules. For example, we will use nano-emulsions or flexible nano-liposomes (consisting of particles < 100 nanometers in size) to incorporate or encapsulate the molecules we wish to deliver. In this way, the nanosystems act as “Trojan horses” to allow the active substances to by-pass the skin barrier.

Our first goal is to understand the physical and chemical properties of selected nanosystems that enable them to be used for this purpose, as well as their toxicity. This will allow us to make predictions about their effectiveness and to design nanosystems for particular purposes. With this kinowledge, we can then apply them to achieve specific

targeting of cells in different skin regions with minimal skin disruption.

Potential outcomes of the research:Our work will allow us to exploit new, minimally-invasive delivery routes for a variety of stains, drugs and vaccines into the underlying viable skin target layer. New insights gained will lead to significant patient and health professional outcomes, including better rapid, non-invasive skin disorder diagnoses, better photodynamic therapy, less invasive vaccine therapy and potential improvements in therapeutic and cosmetic therapies.

Professor Michael RobertsNHMRC Project Grant

Professor Michael Roberts, Professor Darrell Crawford, Professor Guy Maddern

Advanced imaging to define hepatic & intestinal drug disposition in aging & liver diseases($735,820 University of South Australia)

Our research project:In this project, we will image drug levels in the liver and intestine of rats and mice after making the incision in abdominal cavity. Imaging will be done by absorption, reflectance and fluorescence confocal and multiphoton microscopy in space and time with a resolution less than1 μm. We will seek to observe and integrate the movement of drugs from the sinusoid into the hepatocyte or enterocyte, metabolism in the cell and efflux from the cells in different liver zones and relate with microcirculatory changes. We will use this approach to explore mechanisms by which drug detoxification in the gut and liver are modified by ageing, liver disease and drug toxicity in vivo. We propose to also estimate organ concentrations to enable the findings to be scaled-up to human and to validate these findings by whole body (positron emission tomography (PET), fluorescence) and appendage

(LiMon) imaging studies.

Potential outcomes of the research:The significance of our proposal lies in using non-invasive imaging to facilitate personalized dosing. The desired outcomes of current project are establishing the suitable in vivo imaging techniques and finding the suitable fluorescent markers and conditions for non-invasive imaging of liver and intestinal function.

Professor Pamela RussellNHMRC Project Grant

Professor Pamela Russell, Professor Andrew Whittaker, Dr Kristofer Thurecht

Simultaneous Imaging and Drug Delivery for Prostate Cancer Theranostics($545,362 Queensland University of Technology)

Our research project:Over 20,000 Australian men develop prostate cancer resulting in 3,500 deaths per year. Clinical decisions for managing patients with advanced prostate cancer require precise information concerning their response to therapy, posing several challenges. Biochemical testing of serum prostate specific antigen (PSA) levels is usually done along with bone scans; determining a response can take several weeks. As some treatments have nasty side effects and not all patients respond, an alternative is to target the drug to the tumour and visualize treatment response in a rapid fashion by imaging.

We have generated a theranostic agent (nanoparticles that diagnose and treat cancer) based on hyperbranched polymers that show good imaging in vivo via 19F-MRI, are non-toxic and can be functionalized to target a prostate cancer surface antigen to detect, stage and treat prostate cancer, and image the response to treatment. Drug release occurs once the polymers are taken up by cancer cells, facilitating effective, specific uptake at the desired cell-site whilst avoiding systemic side effects. This unique coupling 19F-HP with targeted drug delivery can provide sensitive, specific imaging for advanced theranostics. The hyperbranched polymers are very flexible and can be changed to accommodate new targeting agents, or new drug therapies as they become available to assist in patient

management.

Potential outcomes of the research:Our proposal involves discovery, development, and preclinical validation of new, non-invasive tests based on a directly targeted contrast agent to detect prostate cancer. If this succeeds, we will have created a platform technology that could be exploited for diagnosis/locoregional staging of prostate cancer, and surveillance of patients on watchful waiting. This agent will also deliver targeted treatment by incorporating cytotoxic agents, and allow for early assessment of treatment response.

Dr Raymond SteptoeNHMRC Project Grant

Dr Raymond Steptoe, Dr Janet Davies

A new and effective approach to reversal of allergic airways inflammation by turning off allergic responses($379,931 The University of Queensland)

Our research project:Inflammatory diseases like asthma develop from misdirected immune responses. The ultimate goal of therapeutic strategies is to remove or inactivate the cells that cause inflammation while leaving other cells, for example, those required for protection from infectious diseases and tumours, unaffected. Here we propose to test a new way of turning off the inappropriate immune reaction with the goal of preventing or reversing asthma. Asthma is a chronic inflammatory disease of the lower airways caused primarily by dysregulated CD4+ T-cell responses to inhaled environmental allergens and is the most prevalent cause of significant respiratory morbidity in the developed world. Immunotherapies embody the potential to terminate pathogenic T-cell responses and are a promising path to disease reversal and/or prevention. As the airway inflammation underlying asthma is ‘driven’ by established populations of pathogenic effector and memory T cells, effective reversal of disease requires a means to ‘turn-off’ (tolerise) these cells but there has been a lack of understanding of how to effectively achieve this. We discovered that effector and memory T cells are highly susceptible to tolerance induction when antigen is genetically targeted to dendritic cells (DC) and extended this to demonstrate that antigen-encoding hematopoietic progenitor cells (HPC) can be used specifically as a tool to turn off effector and memory T-cell responses underlying allergen-induced airways inflammation (AAI).

The major challenge in any immunotherapy is to address established pathogenic effector and memory T cells. In order to understand what is required to facilitate practical and effective immunotherapies in a clinical setting, we will define the mechanisms and requirements underlying the effective means we have found to ‘turn-off’ allergen-specific effector and memory T cells responses

Potential outcomes of the research:Asthma is a chronic disease with onset most often in childhood or adolescence but effects last well into adulthood. Approximately 20% of Australians will suffer asthma at some stage during their lifetime. No cure is available and current therapies provide symptomatic relief but do not alleviate the burden of complications associated with this disease. The incidence of asthma is rising at an alarming rate. The estimated annual cost to the Australian health care system (excluding indirect economic cost) was $0.8b in 2007 and this will increase as the population ages due to the persistent chronic course of the disease.Development of a cure for this chronic disease, which is the goal of this proposal, would considerably ease the burden on the health care system and the personal, social and economic damage inflicted by this disease.

Dr Raymond SteptoeNHMRC Project Grant

Dr Raymond Steptoe

Reversing autoimmune diabetes by controlling pathogenic effector T-cells($394,556 The University of Queensland)

Our research project:Type 1 Diabetes (T1D) results from misdirected immune responses that destroy insulin-producing pancreatic cells. The ultimate goal of therapeutic strategies is to remove or inactivate the cells that attack insulin-producing cells, while leaving other cells, for example, those required for protection from infectious diseases and tumours, unaffected. Here we propose to test a new way of turning off the inappropriate immune reaction with the goal of

preventing Type 1 Diabetes.

Potential outcomes of the research:Type 1 Diabetes (T1D) is a chronic disease with onset most often in childhood or adolescence. With it comes substantial complications that arise from a lifetime of imperfect glycemic control. No cure is available and current therapies provide symptomatic relief but do not alleviate the burden of complications associated with this disease.

The incidence of T1D is rising at an alarming rate and the estimated direct cost to the Australian health care system (excluding indirect economic cost) is $1.5b. Development of a cure for this chronic disease, which is the goal of this proposal, would considerably ease the burden on the health care system and the personal, social and economic damage inflicted by this disease

Professor John UphamNHMRC Project Grant

Professor John Upham, Dr Anthony Bosco, Associate Professor Ian Mackay

Anti-viral immunity in asthma: a detailed assessment of TLR7 function and the regulation of interferon α/β synthesis($499,393 The University of Queensland)

Our research project:Many people with asthma are unusually vulnerable to viral infections, even the common cold viruses (rhinoviruses). This project aims to provide insight into how the immune system protects healthy people from rhinoviruses, and what goes wrong in asthma.

The project will undertake a detailed examination of the immune responses to rhinoviruses in people with asthma and healthy people. We have previously found that people with asthma are less able to produce anti-viral proteins known as interferons. This study will try to find out why. We will examine the genes that regulate anti-viral imunity, the receptors that respond to viral nucleic acids, the molecular pathways inside cells that lead to the production of interferons, and the function of specialised immune cells known as plasmacytoid dendritic cells. This research may lead to novel methods for prevention and

treatment of virus infections in people with asthma.

Potential outcomes of the research:Asthma affects around 10% of the community, and over 400 Australians die each year due to asthma. This research project will lead to better understanding of why people with asthma are vulnerable to virus infections. The findings from the study are likely to produce novel insights into how infections trigger asthma attacks, thus providing an important foundation for improved management and future vaccine development.

Professor Zee UptonNHMRC Project Grant

Professor Zee Upton, Dr Michael Doran, Associate Professor Kiarash Khosrotehrani

Innovations in Diabetic Foot Ulcer (DFU) Wound Care($387,711 Queensland University of Technology)

Our research project:A common complication of Types I or II Diabetes is damage to nerves and/or blood vessels (neuropathy and/or angiopathy) resulting in loss of movement/feeling and blood clotting. These complications, coupled with other risk factors, result in those with diabetes having a 12-25% lifetime risk of developing a diabetic foot ulcer. Diabetic foot ulcers are one of the most common complications associated with diabetes, and effective treatment remains a significant and costly challenge. New therapies for diabetic foot ulcer treatment are urgently required.

The three leading emerging technologies for treating diabetic foot ulcer appear to be: (1) application of topical growth factors; (2) artificial platforms on which tissues grow; and (3) mesenchymal stem/stromal cell-based therapies. In this project Professor Zee Upton’s team will capture and combine the strengths of these three technologies within a single

interactive bioscaffold-based therapy.

Potential outcomes of the research:Diabetic foot ulcers precede 85% of all amputations, and those who develop a diabetic foot ulcer have a 5-8% probability of suffering an amputation in the first year. By 5 years post-amputation, 45-55% of patients will die. The bio-scaffold proposed harnesses the therapeutic potential of the most promising diabetic foot ulcer technologies available and in doing so, offers a unique solution to a largely unsolved challenge.

Professor Peter VisscherNHMRC Project Grant

Professor Peter Visscher

Exploiting SNP data in epidemiology and genetics through multivariate analysis of complex traits($460,517 The University of Queensland)

Our research project:There is overlap in risk factors across multiple diseases, and some of that overlap is due to genetic factors. The availability of genome-wide DNA data on tens of thousands of patients for multiple diseases and healthy controls allows new questions to be asked and answered. For example, what is the overlap due to genes in disease risk for multiple sclerosis and rheumatoid arthritis?

This project will develop and statistical genetic methodology to answer such questions and

apply those methods to a range of important disease.

Potential outcomes of the research:This proposal is about exploiting the availability of large datasets with genetic and phenotypic data to address new and important questions in genetics and epidemiology of complex diseases in humans. (Arthritis and Musculoskeletal, Cardiovascular Health, Diabetes, Mental Health).

Professor Peter VisscherNHMRC Project Grant

Professor Peter Visscher, Professor Grant Montgomery

CAGE: Consortium for the Architecture of Gene Expression($484,190 The University of Queensland)

Our research project:This research project is about understanding why some people are most susceptible to disease than others, by identifying genetic factors that influence the expression of genes that are important in disease. We will work with leaders in the field in Europe and the USA in an international research consortium to find genetic variants with an effect on gene expression and to link those genetic factors to disease. The project will provide new

understanding about the biological basis of common diseases.

Potential outcomes of the research:We have pioneered the use of multi-marker statistical genetic methods in human genetics to elucidate the genetic architecture of complex traits1-6. We have built a resource to detect expression QTL in human tissues7,8. We wish to build upon and leverage these foundations to map cis and trans effects on gene expression using large experimental sample sizes, and investigate how these effects influence medically relevant traits. Therefore, understanding the genetic basis of gene expression is likely to lead to a better understanding of genetic variation of quantitative traits and risk factors for common diseases and for disease itself.

Dr Timothy WarrenNHMRC Postgraduate Scholarship

Dr Timothy Warren

Molecular and epidemiological investigation of cutaneous squamous cell carcinoma of the head and neck with perineural invasion($38,079 Princess Alexandra Hospital)

Our research project:Queensland has the highest recorded rates of skin cancer in the world. Invasion into nearby nerves or ‘perineural invasion’ occurs in approximately 5% of cases. This signifies that the tumour is aggressive and able to spread along nerves back to the brain and reduce survival. Why some tumours invade nerves remains unclear. This project will study the molecular factors involved and the characteristics of affected patients to enable a better understanding of the disease and potentially improve treatment.

Potential outcomes of the research:This research is investigating an area of vital importance to Queensland, which is the skin cancer capital of the world. The project aims to increase the understanding and awareness of skin cancer with nerve invasion, and potentially identify patients at high risk of the disease earlier, which can improve survival outcomes.

Associate Professor Jonathan WhiteheadNHMRC Project Grant

Associate Professor Jonathan Whitehead, Professor Johannes Prins

Defining a new adipogenic pathway($448,514 Mater Medical Research Institute)

Our research project:Obesity increases the risk of developing diseases such as heart disease and type 2 diabetes, however, not all obese people develop such diseases. Obese subjects with small fat cells are typically healthier than those with fewer, large fat cells. The applicants have identified a novel pathway that promotes the generation of new fat cells. This project will increase understanding of this pathway and may, ultimately, lead to new therapies that manipulate fat cell number and reduce obesity related disease.

Potential outcomes of the research:These studies will increase our understanding of the molecular mechanisms regulating commitment and differentiation of preadipocytes, areas of substantial therapeutic interest. They will provide new insights into the importance of the novel BAMBI/CPX-1 pathway in adipocyte hyperplasia and adipose tissue remodelling in obesity. They will also reveal new candidates that may provide the foundation for innovative therapeutic strategies to improve adipocyte function and reduce the metabolic sequelae of obesity, such as cardiovascular disease and type 2 diabetes.

Dr Jian YangCareer Development Fellowship

Dr Jian Yang

Dissecting genetic variation for human complex diseases and traits($397,724 The University of Queensland)

Our research project:Most human complex diseases and traits such as diabetes, cancers, cognitive ability and mental disorders, are influenced by many genes and the interplay of risk variants within and between genetic loci and with environmental factors. Understanding the pattern of inheritance for complex diseases such as cancers, obesity, diabetes and mental illness, is of key importance for disease diagnosis, treatment and prevention.

The aim of this project is to develop novel methods and software tools to address fundamental questions in genetic studies of complex diseases and traits, e.g. the importance of rare variants and non-additive genetic variation, providing important knowledge for future research in gene discovery, and to improve genomic risk prediction, a key element of genomic medicine.

Potential outcomes of the research:This project will provide new knowledge to inform strategies and designs for future research in human complex diseases, and the delivery of new user-friendly software tools freely available for public use. The application of the methods to a wide range of complex diseases and traits will shed more light on the genetic architecture of many medically important diseases and traits.

In addition to their participation in many of the prestigious projects already highlighted in this brochure, Diamantina Health Partner members will be affiliated with the following projects:

Mater Medical Research Institute (MMRI) / Murdoch Children’s Research InstituteAssociate Professor Philip Sutton, Professor Michael McGuckin (MMRI)Muc1 regulation of the NLRP3 inflammasome in the gastrointestinal tract$429,014.

Menzies School of Health ResearchProfessor Anne Chang, Professor John Upham (UQ SOM/PAH), Professor Peter Gibson, Dr Stephanie Yerkovich, Dr Katherine Baines, Associate Professor Sandra Hodge, Mrs Susan Pizzutto, Associate Professor Ian Masters, Dr Helen BuntainProtracted bacterial bronchitis: long term outcomes, systemic and airway predictors of recurrence$777,376

Assoc Professor Patricia Valery, Associate Professor Gail Garvey, Professor Ross Bailie, Associate Professor Euan Walpole (PAH), Professor Jonathan Adams, Mr Daniel Williamson, Associate Professor Jennifer Martin (UQ SOM/PAH)Improving systems and quality of cancer care in Aboriginal and Torres Strait Islander primary health care settings$617,502

Queensland Institute of Medical Research (QIMR)Associate Professor V Nathan Subramaniam, Dr Daniel Wallace, Associate Professor, Jonathan Harris, Professor Carlos Lopez-Otin, Associate Professor John Hooper (MMRI)Dissecting the TMPRSS6 regulation of iron homeostasis$592,142

The University of AdelaideProfessor Mark Bartold, Professor Stan Gronthos, Professor Saso Ivanovski, Professor Dietmar Hutmacher (QUT)Comparison of periodontal ligament stem cells and induced pluripotent periodontal ligament stem cells for periodontal regeneration$802,470

Professor Richard D’Andrea, Professor Thomas Gonda (UQ PACE), Dr Anna Brown, Associate Professor Ian LewisIdentification and characterisation of novel FLT3-ITD co-operating mutations$636,662

The University of MelbourneProfessor Danny Rischin, Associate Professor June Corry, Associate Professor Richard Fisher, Professor Madeleine King, Associate Professor Sandro Porceddu (PAH)A randomized trial of radiation with cetuximab or weekly cisplatin in low risk locoregionally advanced HPV-associated oropharyngeal cancer$1,097,932

The University of SydneyAssociate Professor Trevor Leong, Professor John Zalcberg, Professor Carol Swallow, Professor Florian Lordick, Associate Professor Bernard Smithers (PAH/UQ SOM), Professor Val Gebski, Associate Professor Alex Boussioutas, Professor Karin Haustermans, Professor Rebecca Wong, Associate Professor Michael MichaelA randomised phase III trial of preoperative chemoradiotherapy vs preoperative chemotherapy for resectable gastric cancer$1,974,558

The University of Queensland Dr Marcel Dinger, Professor Grant Montgomery, Associate Professor Brian Gabrielli (UQDI)Functional characterization of the regulatory architecture of melanoma-associated loci$624,298

Dr Jason Roberts, Professor Jeffrey Lipman, Professor Michael Roberts (UQ SOM), Associate Professor Sanjoy Paul (UQ), Associate Professor Sandra Peake, Professor John TurnidgeRobust antibiotic dosing for critically ill patients receiving renal replacement therapy$1,034,978

University of TasmaniaDr James Sharman Associate Professor Walter Abhayaratna, Professor Michael Stowasser (UQ SOM/PAH)Targeted LOWering of Central Blood Pressure in patients with hypertension: a randomised controlled trial (LOW CBP study)$1,384,301

Victor Chang Cardiac Research Institute LimitedProfessor Sally Dunwoodie, Dr Duncan Sparrow, Associate Professor Emma Duncan (RBWH/UQDI)Determining the causes of congenital vertebral defects$926,275

Diamantina Health Partners is Queensland’s first academic health sciences centre, bringing together the State’s leading hospitals and universities to improve care for patients in our community. The partners include the following organisations:

• Princess Alexandra Hospital • Mater Health Services • The University of Queensland • Queensland University of Technology • Translational Research Institute • UQ Health Care (GP superclinics) • Metro South Mental Health • Inala Indigenous Health Service

Together, we aim to seek excellence in health outcomes through integration of clinical delivery, research and education.

PrincessAlexandraHospital

Mater Health Services

Translational ResearchInstitute

The University of Queensland

Queenland University of Technology

Metro South Mental Health

UQHealth Care

Inala Indigenous Health Service

Diamantina Health Partners disseminates worthy news of grant success and research achievements.Please contact Ms Areti Gavrilidis, DHP Executive Consultant, on:

Telephone (07) 3443 8063Email areti.gavrilidis@diamantina.org.auAddress Level 7, Translational Research Institute 37 Kent Street Woolloongabba, QLD, 4102Web http://diamantina.org.au

©Diamantina Health PartnersThis work is copyright. Apart from any use as permitted under the Copyright Act 1968, no part of this publication may be reproduced by any process

without prior written permission from Diamantina Health Partners . Enquiries should be directed to information@diamantina.org.au