Japanese Encephalitis Virus In Australasia: Molecular Studies Of Isolates And Consequences Of Immunisation.
Funder
National Health and Medical Research Council
Funding Amount
$212,036.00
Summary
Japanese encephalitis (JE) virus is a mosquito-transmitted virus of Asia. Infection causes clinical disease in about 1 in 50 people infected, and of these, about 25% will die from a fatal encephalitis (inflammation of the brain), and a further 50% will have lifelong severe disabilities. There are over 50,000 cases annually in Asia, with about 12,000 fatalities.The virus normally circulates between mosquitoes and water birds and between mosquitoes and pigs. The World Health Organization has recog ....Japanese encephalitis (JE) virus is a mosquito-transmitted virus of Asia. Infection causes clinical disease in about 1 in 50 people infected, and of these, about 25% will die from a fatal encephalitis (inflammation of the brain), and a further 50% will have lifelong severe disabilities. There are over 50,000 cases annually in Asia, with about 12,000 fatalities.The virus normally circulates between mosquitoes and water birds and between mosquitoes and pigs. The World Health Organization has recognised JE as one of the most important mosquito-borne viruses because of its propensity to spread and to colonise new areas. The virus first appeared in northern Australia in the Torres Strait in 1995, causing three clinical cases of whom 2 died, and returned again in 1998, with a further case in the Torres Strait and the first case to occur on mainland Australia in Cape York. Both of these patients recovered. The virus returned again to the Torres Strait in 2000, but so far without causing human disease. We have shown that the virus is established in Papua New Guinea (PNG), where it is spreading rapidly, and our results suggest that PNG was the source of the virus causing the outbreaks in 1995 and 1998. It is believed that JE virus will almost certainly become established in Australia within the next few years. The aims of this project are to explore the consequences of JE becoming established and specifically: (a) the use of inactivated JE vaccine to protect at-risk populations and whether the vaccine will provide sufficient protection or whether it will lead to enhanced infection with indigenous flaviviruses such as Murray Valley encephalitis virus; and (b) the possibility of emergence of genetic variants with increased transmissibility, virulence, and altered neutralisation epitopes.Read moreRead less
The Role Of Specific Nox Isoforms In Diabetic Renal Disease And Atherosclerosis
Funder
National Health and Medical Research Council
Funding Amount
$460,396.00
Summary
Diabetes is increasing worldwide and in Australia. The majority of patients with diabetes eventually will develop kidney disease and will die of blood vessel complications such as heart attacks and stroke. Oxidative stress (the generation of free oxygen radicals that react quickly with other proteins in the body causing tissue damage) has been suggested to play an important role in kidney and blood vessel disease observed in diabetic patients. This proposal will try to identify and measure speci ....Diabetes is increasing worldwide and in Australia. The majority of patients with diabetes eventually will develop kidney disease and will die of blood vessel complications such as heart attacks and stroke. Oxidative stress (the generation of free oxygen radicals that react quickly with other proteins in the body causing tissue damage) has been suggested to play an important role in kidney and blood vessel disease observed in diabetic patients. This proposal will try to identify and measure specific proteins in the kidney and vessels that are involved in the production of oxidative stress. We aim to define which one of these proteins is the most important. We will assess in detail how these proteins work and which other factors are activated leading to tissue damage. The ultimate goal of these studies is to find new treatment options to decrease the production of harmful molecules in the kidney and blood vessel wall thereby reducing kidney failure, heart attacks, stroke and gangrene in diabetes. In our studies, we will use medications already used in patients to treat high blood pressure in diabetes. In preliminary studies we have shown that these drugs also reduce oxidative stress. Furthermore, we will use novel, more specific treatments that the harmful ptoteins. Through a collaboration with Professor Harald Schmidt and his group from Germany who have recently moved to Monash University in Melbourne we will have access to mice in which specific genes for harmful proteins have been knocked out. These mice when made diabetic will most likely develop less or no kidney and blood vessel damage. Our studies will help to identify the most important oxidative stress producing protein associated with kidney and vessel disease. This knowledge will lead to more effective and more potent treatments for patients with diabetes to prevent, stop or even improve kidney and blood vessel disease thereby reducing disability and death in this high risk group of patients.Read moreRead less
Defining The Roles Of NADPH Oxidases In Vascular Remodelling And Arterial Hypertension
Funder
National Health and Medical Research Council
Funding Amount
$401,523.00
Summary
Hypertension (high blood pressure) is a major risk factor for cardiovascular diseases such as heart attacks, heart failure and stroke - the major causes of death world-wide and a huge burden on the Australian health care budget. Oxidative stress, resulting from an imbalance in the production and removal of toxic molecules called free radicals within the blood vessel wall, is a key player in the initiation and progression of these disorders. In the early stages of hypertension, production of free ....Hypertension (high blood pressure) is a major risk factor for cardiovascular diseases such as heart attacks, heart failure and stroke - the major causes of death world-wide and a huge burden on the Australian health care budget. Oxidative stress, resulting from an imbalance in the production and removal of toxic molecules called free radicals within the blood vessel wall, is a key player in the initiation and progression of these disorders. In the early stages of hypertension, production of free radicals only just outweighs their removal, resulting in a mild oxidative stress. However, this is enough to trigger a cascade of downstream events leading to activation of other, normally dormant, free radical generating systems. At these excessive levels, free radicals attack the cells of the artery wall leading to blood vessel dysfunction and ultimately cardiovascular disease. A major source of free radicals in the blood vessel wall are a family of enzymes called NADPH oxidases. It is our hypothesis that upregulation of onr of these enzymes in the early stages of hypertension is the initial trigger for many of the downstream effects that ultimately lead to cardiovascular disease. Our group is uniquely poised to test this hypothesis as we are the only laboratory in the world with access to three different strains of genetically modified mice, each lacking one of the three known isoforms of NADPH oxidase. Identification of the specific isoform of NADPH oxidase involved in free radical production in blood vessels is a critical first step in developing drugs that block vascular free radical production and so remove the molecular link between hypertension and major cardiovascular events.Read moreRead less
Mitochondrial Complex II Is A New Target For Anti-cancer Drugs
Funder
National Health and Medical Research Council
Funding Amount
$448,434.00
Summary
Cancer is a huge problem and is most likely to get worse. Therefore, new approaches to treatment are necessary. Cancer cells constantly mutate, so many established drugs cannot be used. A very promising approach is targeting mitochondria, the powerhouse of the cells. This is because these organelles are important for all cancer cells. We are proposing a novel way of using mitochondria as targets for a group of anti-cancer drugs that would ultimately result in efficient cancer management.
Formation of clots to prevent blood loss is initiated by the platelet receptors, glycoprotein (GP)Ib-IX-V and GPVI. Unfortunately, there is a gap in our knowledge regarding the events immediately following activation of these receptors and the known downstream signalling. We have identified a novel binding partner for these platelet receptors, which we believe links reactive oxygen species to platelet signalling events. This opens new avenues for therapies to prevent aberrant clotting.
Nitroso-redox Imbalance In Glucocorticoid-induced Hypertension
Funder
National Health and Medical Research Council
Funding Amount
$341,210.00
Summary
High blood pressure (hypertension) affects 20-30 % of Australian adults and in about 90-95 % of these individuals the hypertension is considered essential (cause unknown). Globally, it is the number 1 risk factor for death, and number 3 for disability (World Health Report 2002). The major consequences of hypertension are heart attack and stroke. Glucocorticoid (adrenal steroid hormone) induced hypertension and consequent cardiovascular morbidity-mortality is an important clinical problem. Althou ....High blood pressure (hypertension) affects 20-30 % of Australian adults and in about 90-95 % of these individuals the hypertension is considered essential (cause unknown). Globally, it is the number 1 risk factor for death, and number 3 for disability (World Health Report 2002). The major consequences of hypertension are heart attack and stroke. Glucocorticoid (adrenal steroid hormone) induced hypertension and consequent cardiovascular morbidity-mortality is an important clinical problem. Although naturally occurring glucocorticoid (GC) hypertension (Cushing's syndrome) is relatively rare, synthetic GC are widely used in clinical practice (in numerous inflammatory and autoimmune diseases and transplantation) and produce substantial cardiovascular morbidity and mortality. Further, abnormal GC breakdown (metabolism) and sensitivity to GC have been reported in around a third of essential hypertensive patients. We therefore need to understand how GC raise blood pressure and whether we can prevent and-or reverse these blood pressure raising effects. In the proposed studies, we will explore the role of relative deficiency of blood vessel dilating nitric oxide and nitric oxide inhibition by excess superoxide (nitroso-redox imbalance) in the genesis of GC hypertension. Further, we will identify agents known to be suitable for clinical use which are effective in preventing-reversing GC hypertension in the rat and are thus appropriate for clinical trials to prevent-reverse GC hypertension in humans. These studies will help answer the question of how GC raises blood pressure so that safer steroids can be designed, as well as identify agents that can potentially prevent or treat GC hypertension in humans.Read moreRead less
How Does Oxygen Regulate Ca2+ Channel Function In Cardiac Myocytes?
Funder
National Health and Medical Research Council
Funding Amount
$475,517.00
Summary
Oxygen occupies a key role in cellular metabolism and function. Oxygen delivery to cells is critical and lack of oxygen such as occurs during a heart attack can be lethal. Death occurs commonly by induction of arrhythmia or a disturbance in the heart beat. The abnormal heart beat cannot enable the heart to pump blood efficiently and vital organs are then deprived.Exactly how arrhythmia is induced is not understood. The normal heart beat occurs as a result of propogation of electrical signals thr ....Oxygen occupies a key role in cellular metabolism and function. Oxygen delivery to cells is critical and lack of oxygen such as occurs during a heart attack can be lethal. Death occurs commonly by induction of arrhythmia or a disturbance in the heart beat. The abnormal heart beat cannot enable the heart to pump blood efficiently and vital organs are then deprived.Exactly how arrhythmia is induced is not understood. The normal heart beat occurs as a result of propogation of electrical signals through heart muscle cells. The electrical activity is generated and sustained by movement of salts or ions through membrane proteins known as ion channels. One of these channels, the L-type calcium channel plays a vital role in cardiac excitation and contraction. A reduction in oxygen alters the function of the L-type calcium channel. However, the exact mechanism for this is uncertain. An oxygen sensing mechanism in the cell is responsible for the regulation of channel function during hypoxia. The exact identity of the oxygen sensor is currently the centre of debate. Four hypotheses have been proposed. This proposal aims to examine in detail the four hypotheses of oxygen sensing to definitively determine the identity of the oxygen sensor. This information should increase our understanding of how calcium channels function during stressful conditions such as during a heart attack.Read moreRead less
The Role Of Glutathionylation In Redox Modification Of L-type Ca2+ Channel Function During Oxidative Stress In The Heart
Funder
National Health and Medical Research Council
Funding Amount
$402,898.00
Summary
The L-type calcium channel is a protein in the membrane of heart muscle cells responsible for regulating the entry of calcium into cells and maintaining normal heart rhythm and contraction. We have shown that reactive oxygen species can regulate the function of the calcium channel. We are now interested in determining whether a direct modification of the channel protein known as glutathionylation is responsible for altered channel function during oxidative stress such as after a heart attack.
Regulation Of Insulin Sensitivity By Reactive Oxygen Species
Funder
National Health and Medical Research Council
Funding Amount
$564,644.00
Summary
In morbid obesity and type 2 diabetes chronic levels of reactive oxygen species (ROS) are detrimental and diminish insulin's ability to maintain normal blood glucose levels. Paradoxically, ROS also promote insulin action by inhibiting enzymes known as protein tyrosine phosphatases (PTPs). This proposal will determine whether the promotion of ROS for the inhibition of PTPs early in the progression of type 2 diabetes may be of therapeutic benefit.