Freemasons Foundation Grant
Associate Professor Johanna M Montgomery, Physiology
‘Plasticity in the heart and its role in atrial fibrillation’
$259,848
The ability of neurons to change their strength of communication is known as “plasticity”. In the brain, plasticity plays a critical role in cognitive, sensory, and motor functions. But what role does plasticity play in the large numbers of neurons located outside of the brain? On the surface of the heart are ~14,000 neurons which are grouped in clusters termed ganglionated plexi (GP) or “little brains”, and they play a critical role in the most common pathological heart rhythm, atrial fibrillation (AF).
AF is associated with significant clinical consequences including a 5-fold increase in stroke, a 3-fold increase in heart failure, and a doubling of risk for dementia. In this proposal Associate Professor Montgomery will apply her detailed knowledge of synapses and plasticity in the brain to the fundamentals of plasticity in the “little brains” of the heart to determine how this plasticity contributes to AF. Using a rodent model of arrhythmia, the multidisciplinary team of Montgomery, Paton and Smaill will utilise precise physiology techniques to identify the patterns of electrical hyperexcitability in GP neurons during AF. They will also apply super-resolution imaging techniques to reveal how AF could drive ultrastructural changes in GP synapses. Together these data will determine how plasticity in the peripheral neurons of the heart regulates the function of this vital organ.
2018 Breast Cancer Research in New Zealand Partnership
Dr Dean Singleton, Auckland Cancer Society Research Centre
‘Targeting HIF-1 in Triple Negative Breast Cancer using glutaminase inhibitors’
24 months, $237,494
Low-oxygen (hypoxia) is a common feature of breast tumours that is associated with aggressive disease outcomes and poor patient survival. Hypoxia is “sensed” in cells by a protein called hypoxia-inducible factor 1 (HIF-1). HIF-1 accumulation in oxygen-deprived cancer cells encourages tumour growth by stimulating new blood vessels and causes cancer cells to become invasive and resistant to anticancer therapy. Interestingly, most triple negative breast cancers (TNBC) make and secrete excessive amounts of the amino acid glutamate. Glutamate accumulation in the tumour interferes with uptake of cysteine and this causes activation of HIF-1, even when oxygen is abundant. Using drugs to block de novo glutamate production (glutaminase inhibitors) Dr Singleton and his team demonstrated reduced glutamate secretion and improved degradation of HIF-1 in cell culture models of TNBC. Glutaminase inhibitors are showing impressive clinical activity in studies of heavily treated, therapy-resistant TNBC. Dr Singleton’s project aims to further characterise the changes in cell metabolism that contribute to increased HIF-1 degradation following glutaminase inhibition. The potential of using HIF-1 modulation as a predictive biomarker of treatment response will also be assessed using TNBC tumour xenograft studies.
2018 Breast Cancer Register Partnership
Dr Annette Lasham, Molecular Medicine and Pathology
‘Analysis of DCIS data in the National Breast Cancer Register’
12 months, $117,217
Summary: Ductal carcinoma in situ (DCIS) accounts for about 20% breast cancers and represents cancer cells confined within the normal structures of the breast. In up to 40% of patients, invasive breast cancer (IBC) develops with the potential to cause death. Doctors currently cannot predict which DCIS will develop IBC and consequently all DCIS patients are treated as if it will. The DCIS Breast Cancer Register project proposes to analyse the National Breast Cancer Register for information pertaining to all DCIS cases. They will analyse this data using various statistical methods, with the priority to look for factors associated with NZ DCIS patients developing IBC. They will compare their findings to those from international studies. They will then build a statistical model to see if combining certain types of information can be used to predict the risk of DCIS patients developing IBC. The findings of this study may be useful in influencing clinical decisions in the future.