Stunning NHMRC Grant success

Enhancer RNAs (eRNAs) are a new class of noncoding RNA molecules that have been linked to diverse functions that impinge on cancer, but their clinical relevance is unknown. This project uses sophisticated preclinical models and cutting edge technology to investigate the functional role of enhancers and enhancer templated RNA in cancer.

Our naturally occurring gut bacteria, our microbiota, can provide health benefits or cause disease depending on the circumstance. Through this research Dr Forster seeks to identify when these bacteria represent a risk to a patient and should be removed and when they could be beneficial and should be added to induced a desirable immune response.

The steroid hormone aldosterone controls salt balance and hence, blood pressure. It also has been shown to have a significant role in cardiac failure. Although drugs that block the aldosterone receptor are beneficial in the treatment of heart failure, they are limited by potassium retention in the kidney. In order to develop tissue-specific blockers of the aldosterone receptor, it is necessary to identify mechanisms by which the receptor can be activated and/or blocked in these tissues.

Bacterial lung infections are a serious cause of illness and death in humans. To fight infection, the body activates the immune system using a network of signalling molecules. We are studying exactly how one of these signalling molecules, called interferon, controls the infection. Interferon induces the killing of bacteria that are replicating inside human lung cells. How interferon drives bacterial death is not known and this will be studied in this proposal.

The immune response in the female reproductive tract is influenced by the microbiome, specialised cells and hormone surges to fine-tune protection from disease, yet facilitate pregnancy. We will discover how these factors influence a new regulatory protein we discovered and called interferon epsilon, to assist its use in infections and inflammatory diseases affecting women’s health.

Stomach cancer is the third most lethal cancer worldwide, and is strongly associated with inflammation (gastritis) caused by Helicobacter pylori bacterial infection. However it remains unknown how Helicobacter triggers gastritis and stomach cancer in people. Using a mouse model for gastritis-associated stomach cancer, our aim is to demonstrate the role of immune system proteins in the stomach which detect bacterial and host DNA to drive chronic inflammatory responses that lead to stomach cancer.

Emphysema is a chronic lung disease that is caused by dysregulation of the immune system, leading to inflammation and destruction of lung tissue. Although emphysema is associated with cigarette smoking, the key components of the immune system which promote emphysema remain ill-defined. Using elaborate mouse models for emphysema, together with biopsies from emphysema patients, our aim is to reveal the role of a protein complex in the immune system called the inflammasome in driving emphysema.

Babies who are born extremely premature can develop a life threatening chronic lung disease that is expensive to treat and even survivors can have lifelong complications. We believe that stem cells release naturally occurring nanoparticles, called exosomes, that can reverse this disease. This represents the next-generation of cell-free regenerative medicine.

Seizures are the most distinctive and frequent indication of neurological abnormalities in newborn infants and are more common in the neonatal period than at any other stage in life. Despite evidence of the limited effectiveness and potential neurotoxicity of current anti-seizure medication, treatment has not changed for decades. We will examine novel treatments that are less toxic and more effective, specifically designed and assessed for neonates.

Embryo implantation is a critical step in establishing pregnancy, requiring stable attachment of an embryo to the uterus. To date, little is known about the interactions between the two players that determine a successful implantation in the human. This project will investigate novel pathways that human embryos use to drive implantation. The study is important for fertility treatment.

Neonatologists are adept at keeping extremely premature babies alive. But the price is a rising incidence of life-threatening diseases that include necrotising enterocolitis (NEC), a progressive and destructive intestinal inflammation that may require surgery, after which just 30 per cent survive. We have created highly potent variants of the anti-inflammatory molecule interleukin 37 whose actions will improve our understanding of NEC pathogenesis and reveal their therapeutic potential in NEC.

Systemic lupus erythematosus (SLE) is an incurable autoimmune disease that affects 5 million patients worldwide, mostly young women. Grave multi-organ inflammation and substantial mortality render SLE a critical unmet medical need. We have found that the immune system molecule interleukin 38 disables several signalling pathways essential for SLE progress. We will explore regulation and function of this molecule in cells from healthy people and SLE patients and in models of the disease.

Cytokines are messenger proteins that function as master regulators of biological processes; thus they play central roles in many diseases. The rare cytokines that block inflammation do so by dampening the immune system’s potentially destructive force, making them attractive targets for drug development. We showed that interleukin 37 is a powerful anti-inflammatory cytokine, and will now evaluate its mechanisms of action and its efficacy against several severe diseases, including cancer.

Dr Pearson hopes to identify previously unknown mutations in our gut and immune cells that can lead to severe inflammation and damage in the intestine. This will provide essential knowledge to help design future therapies for the millions of people worldwide suffering from disorders such as Inflammatory Bowel Disease.

The research investigates systemic lupus erythematosus, which is a condition where the immune system attacks normally healthy tissues. In this disease there is overproduction of interferons that are thought to drive pathology. We have identified factors that control interferon production and will attempt to exploit this to develop new treatments for lupus.

One in every six Australian couples seek infertility treatment. For each IVF cycle, around 20 per cent result in live birth, with these low statistics largely due to failed embryo implantation. Nano-vesicles, released by the womb lining and taken up by the pre-implantation embryo, improve implantation potential. Defining precisely how these vesicles are taken up and act will enable their manipulation to better manage infertility.

Non-genetic (epigenetic) changes in sperm and eggs can alter outcomes in offspring, but the processes involved are poorly understood. By determining the mechanisms that regulate epigenetic inheritance, this project will improve our understanding of how epigenetic changes in the parent can mediate adverse health outcomes in our children.

New pharmaceuticals have been developed that inhibit epigenetic pathways in cells. These pathways significantly affect growth and development in offspring and may represent a risk to future children of patients taking the drug. This project will determine these risks and provide data for developing clinical guidelines for safe use of the drugs.

This project has the potential to provide fundamental insight into the molecular mechanisms underpinning successful RNAi therapy for β‑thalassaemia. We anticipate that lentiviral β-globin gene therapy vectors supplemented with α-globin-specific RNAi sequences can limit the toxic effects of free α-globin and reduce the need for high-level β-globin gene expression. We believe this approach will be more effective than β-globin transgene expression alone.

Sperm microinjection (ICSI) is the commonest assisted reproductive treatment (ART) for severe male infertility. This project aims to assess the general and reproductive health of the first wave of Australian males born using ICSI. More than 700 parents and young men will be invited to participate. This study will provide essential safety information for prospective couples, ART units and government.

Eggs with too few copies of mitochondrial DNA either fail to fertilise or arrest during early development. By supplementing eggs with mitochondrial DNA, we have been able to enhance embryo quality and gene expression profiles. By breeding the offspring derived from eggs given mitochondrial supplementation, this research will determine if they and their progeny meet normal developmental milestones, regulate the transmission of mitochondrial DNA appropriately, and are healthy and fertile.

This project aims to examine the evolution of Legionella as an intracellular organism and the mechanisms by which the bacteria evade environmental predation by amoebae. Aside from the advancement of knowledge, expected outcomes of this project include a greater understanding of amoebae. This will provide significant benefits, and this knowledge may be used to develop inhibitors of amoebae growth.

The birth of a compromised infant affects 13 million pregnancies worldwide annually and is the greatest cause of neonatal death, disability and chronic disease. Dr McGillick will identify mechanisms to greatly improve the fetal to neonatal transition in premature babies and babies with under-developed lungs. This research is urgently required to provide the necessary evidence to target interventions in the delivery room to reduce the short- and long-term burden of disease in compromised newborns.

Fetal growth restriction (FGR) is a serious and common complication of pregnancy that is a principal cause of injury to the developing fetal brain. In turn, damage to the developing brain during pregnancy may cause cerebral palsy and other cognitive and behavioural deficits. This proposal builds on Dr Miller’s work to date characterising the mechanisms that contribute to neuropathology in FGR infants, by implementing targeted strategies to protect or repair the FGR brain.

Thalassaemia is the most common blood disorder worldwide. In severe cases, life-long blood transfusions are needed to survive but complications including iron overload and bone disease can occur. Deferasirox, a drug used to treat iron overload has been linked to kidney stones and bone loss in these patients through increased loss of calcium in the urine. The purpose of this study is to investigate whether bone loss can be reversed by using a diuretic or an alternative iron chelator.