Welcome to the Otago School of Medical Sciences
Ultrastructural identification of newly synthesised receptor proteins at activated synapses
1 September 2014
Dr Beulah Leitch recently received $94,446 funding from the Neurological Foundation of New Zealand for her research on Ultrastructural identification of newly synthesised receptor proteins at activated synapses.
The synthesis and incorporation of new receptor proteins into synapses, is essential for the changes in synaptic strength that underlie memories and learning. Recent evidence suggests that new proteins may be synthesised locally in dendrites and incorporated into synapses in response to activity-induced changes. Loss of this local synthesis of new proteins may be linked to human disorders associated with cognitive deficits. This study aims to identify, with ultrastructural resolution, newly synthesized proteins at stimulated synapses, and to investigate if altered local protein synthesis contributes to synaptic dysfunction underlying various brain disorders such as Alzheimer’s disease. This project is in collaboration with Professor Erin Schuman, Director Max Planck Institute for Brain Research (MPIBR), Frankfurt, Germany. Professor Schuman’s lab at MPIBR, have developed cutting-edge technology, to detect newly synthesised proteins within minutes or hours of synthesis. The goal of the collaborative study between Dr Leitch and Professor Schuman labs is to develop and apply this new technology to visualise newly synthesised proteins at synapses in the brain using high-resolution electron microscopy.
Arginine Metabolism and Schizophrenia
28 August 2014
Dr Ping Liu has recently been awarded a $196,430 project grant for her research on Arginine metabolism and schizophrenia.
Schizophrenia is a chronic mental disorder with prominent prefrontal and hippocampal dysfunction. Schizophrenic patients show positive symptoms (e.g., hallucinations, delusions and thought disorder), negative symptoms (e.g., deficits in social interaction, emotion and motivation) and cognitive dysfunction (e.g., impairments of attention and working memory). While the exact cause of schizophrenia is poorly understood, a number of hypotheses (including neurodevelopmental disruption) have been linked to the aetiology and/or pathophysiology of the disease. Maternal immune activation (MIA) is a neurodevelopmental model of schizophrenia based on epidemiological data showing that bacterial or viral infections during the second trimester of gestation increase the likelihood of the offspring developing schizophrenia in adulthood. This model uses a single systemic administration of the synthetic cytokine inducer during mid-gestation to induce MIA in pregnant rats or mice. A number of behavioural and neural features of schizophrenia are evident in MIA offspring, including impaired sensorimotor gating assessed by prepulse inhibition (PPI, a benchmark test in schizophrenia).
L-arginine is an amino acid that can be metabolised to form a number of bioactive molecules. Previous research has identified schizophrenia risk genes encoding neuronal nitric oxide synthase and reported disturbed biosynthetic and signalling pathways linked to arginine metabolism. These findings suggest that altered arginine metabolism may be implicated in the pathogenesis of schizophrenia. Recently, we have demonstrated dramatically altered arginine metabolic profiles in the prefrontal cortex and hippocampus in MIA offspring at 3 months of age. In our recent preliminary work, we found that the activity and protein expression of a key enzyme involved in arginine metabolism was significantly altered in the prefrontal cortex of patients with schizophrenia.
This project will entail both human and animal work to systematically investigate how the brain arginine metabolic profile changes in schizophrenia, and whether a single MIA insult has prolonged effects on behavioural function (such as PPI) and brain arginine metabolism. The information obtained from this research will contribute significantly to our understanding of the role of arginine metabolism in the pathogenesis of schizophrenia and the neurodevelopmental disruption aspect of the disease aetiology. The positive results may lead to the development of new targets for prevention and/or therapeutic intervention of schizophrenia by targeting arginine metabolism.
National Heart Foundation funding for Dr Pete Jones
25 August 2014
Dr Pete Jones was recently awarded $147,004 by the National Heart Foundation of NZ for his project Novel Mechanisms for the Regulation of Cardiac Ca2+-Release Channel (RyR2) Activity in Models of Cellular Stress.
Cardiac disease is one of the largest causes of mortality in Western society and accounts for 30-35% of all deaths in New Zealand. The economic cost of cardiac disease, in the USA alone, is $273 billion annually and represents 17% of national health expenditures, and New Zealand is likely to be proportionately similar. Diabetes is a strong risk factor for cardiac disease and is now the leading cause of death in New Zealand. To design new pharmaceuticals, improve health outcomes and reduce this health and economic burden, it is vital to understand the molecular and cellular basis of cardiac arrhythmias and cardiomyopathies; two of the most of the most prevalent forms of cardiac disease linked to diabetes. A major cause of cardiac dysfunction, arrhythmia and death is the disruption of the coordinated calcium signalling pathways within the cells of the heart. However, how cardiac disease and diabetes disturb calcium signalling largely remains a mystery. A protein pivotal in regulating cardiac cell calcium signalling is RyR2.
This research project will characterise new pathways through which diabetic stressors and cardiac disease alter the function of RyR2. We will identify how RyR2 is modified in disease and then systematically study how each of these modifications alters the function of this protein. This research will unravel the mechanisms by which diabetic stress and cardiac disease ultimately lead to heart failure. This work is the first step required for the identification of new cellular targets for the next generation of cardio-protective drugs which are urgently required.
18 August 2014
Associate Professor Tony Merriman provided the following information on his research program on gout.
Gout results from increased blood levels of the chemical urate that precipitates in the joints and causes painful gout attacks. Gout is of particular relevance to Aotearoa New Zealand due to the high prevalence and severe disease in Māori and Pacific people. Gout is also associated with diabetes, chronic kidney disease and heart disease. Genetic inheritance is important in determining levels of urate and gout, and is known to interact with environmental risk factors such as alcohol, sugary drinks, and diuretics (that lower blood pressure). The goal of this program of research is to precisely understand the genes that are important and how they work with diet and diuretics to influence urate levels and gout. One flagship project is a scan of the entire genome in 1000s of people with and without gout to understand what causes gout in the present of increased levels of urate. We will also investigate whether genetic makeup influences how people respond to the gout drug allopurinol. We anticipate this research will contribute substantially to gout treatment guidelines and increase scientific and medical knowledge and public awareness of the causes, treatment and prevention of gout.
This research involves several international collaborations, with key input from researchers in Europe, the United States and Australia. Key New Zealand researchers are A/Prof Nicola Dalbeth from the University of Auckland and Prof Lisa Stamp from the University of Otago, Christchurch.