Assessing Efficacy Of Polyfunctional Nanoparticles Engineered For The Delivery Of Multiple Therapeutics In Reduction Of Cardiac Ischemia Reperfusion Injury
Funder
National Health and Medical Research Council
Funding Amount
$317,678.00
Summary
A reduction in heart muscle damage after a heart attack is associated with a reduction in heart failure and an increase in life expectancy. However to date many therapeutic agents are not successful at reducing muscle damage because of difficulty in delivering the drugs to the target site. This project will address these delivery issues by making use of multifunctional nanoparticles which will allow for targeted delivery and release of therapeutics directly to damaged tissue following injury.
The Sulphate Anion Protects Against Stroke: Characterisation Of Neuroprotective Potential And Mechanism Of Action.
Funder
National Health and Medical Research Council
Funding Amount
$189,170.00
Summary
Stroke-cerebral ischaemia affects approximately 40,000 - 50,000 Australians every year and is Australia's leading single cause of disability and second greatest cause of death after heart disease. About 25% of people who suffer a stroke die within one month while most survivors are disabled because of impaired speech, memory, thought processes, vision, balance, or motor control of the limbs (paralysis). The direct and indirect cost of stroke to the Australian community is over $2 billion annuall ....Stroke-cerebral ischaemia affects approximately 40,000 - 50,000 Australians every year and is Australia's leading single cause of disability and second greatest cause of death after heart disease. About 25% of people who suffer a stroke die within one month while most survivors are disabled because of impaired speech, memory, thought processes, vision, balance, or motor control of the limbs (paralysis). The direct and indirect cost of stroke to the Australian community is over $2 billion annually. Hence preventing or reducing brain damage following stroke is of fundamental clinical, social and economic significance. A stroke occurs when there is a reduced blood supply to the entire brain (Global ischaemia; eg. cardiac arrest, heart bypass surgery, closed head injury) or when there is a reduced blood supply to a specific region of the brain, usually as a result of a blockage in a brain artery (thrombo-embolic stroke or focal ischaemia). Despite decades of research, there is no totally satisfactory clinical treatment to reduce brain damage following stroke; the search for new treatments is paramount. We have shown that sodium sulphate can prevent brain damage in rat models of focal and global ischaemia. Importantly we demonstrated that sodium sulphate could prevent brain damage when given up to 8 hours after the stroke was induced in the global model. Delayed treatment following stroke is of clinical significance, since most patients do not receive medical attention until several hours after initial stroke symptoms. It is not known how sodium sulphate protects the brain from stroke. This project has three main aims: 1. To determine the how well sodium sulphate treatment protects the brain in rats following stroke. 2. To determine if sodium sulphate treatment can reduce brain damage in the rat model of focal ischaemia when given 4 - 8 hours after the stroke. 3. To determine how sodium sulphate protects the brain from stroke.Read moreRead less
Identification And Characterisation Of Novel Hydroxylases And Their Substrates Involved In Cellular Hypoxic Response.
Funder
National Health and Medical Research Council
Funding Amount
$239,250.00
Summary
The human body is able to sense and respond to changes in oxygen levels. Under low oxygen (hypoxia) individual cells switch on a number of different genes required to increase red blood cell production and blood flow, and decrease oxygen consumption. This may be under environmental situations such as high altitude, but is also an important part of many human diseases, such as heart attack and stroke (where a clot stops blood flow and oxygen delivery) or cancer (where tumours require oxygen for g ....The human body is able to sense and respond to changes in oxygen levels. Under low oxygen (hypoxia) individual cells switch on a number of different genes required to increase red blood cell production and blood flow, and decrease oxygen consumption. This may be under environmental situations such as high altitude, but is also an important part of many human diseases, such as heart attack and stroke (where a clot stops blood flow and oxygen delivery) or cancer (where tumours require oxygen for growth). We have known for sometime that a few key proteins are activated by hypoxia, such as the HIF proteins, and these act as a master switch to turn on numerous other genes. However, the actual oxygen sensors have remained a mystery. Recent research by others and myself has identified a number of the oxygen sensors, which are hydroxylase enzymes that require oxygen. Under normal conditions with ample oxygen they modify the HIF proteins and keep them inactive, but when oxygen is limiting they can't modify the HIFs and the unmodified HIF is active. So far four different oxygen sensors have been identified, but there is strong evidence for more sensors, and they are likely to modify more targets than just the HIFs. This project aims to identify new oxygen sensing hydroxylases and novel targets, and determine what they each do. I already have some preliminary information as to what some of the other oxygen sensors might be and also some of their likely targets. This work should greatly enhance our understanding of how the body responds to hypoxia, both under normal conditions and during disease. These oxygen sensors might also be very useful drug targets. For example, drugs that inhibit these enzymes should increase the activity of the HIF proteins and facilitate a more rapid response by the body to a heart attack or stroke, and thus limit the damage, whereas drugs that activate the enzymes would inhibit the HIFs and be useful in limiting tumour growth.Read moreRead less
Mechanisms Of Cell Death In Focal Cerebral Ischaemia
Funder
National Health and Medical Research Council
Funding Amount
$229,624.00
Summary
Stroke most commonly results from interruption to a major artery in the brain. If not rapidly reversed the reduction in blood flow leads to the death of many cells in the brain tissue. There is currently considerable interest in developing treatments to be used in the early stages of stroke that can reduce cell death. As the extent of cell death is the major determinant of the long-term disabilities from stroke, such treatments are likely to provide considerable benenfits for affected individual ....Stroke most commonly results from interruption to a major artery in the brain. If not rapidly reversed the reduction in blood flow leads to the death of many cells in the brain tissue. There is currently considerable interest in developing treatments to be used in the early stages of stroke that can reduce cell death. As the extent of cell death is the major determinant of the long-term disabilities from stroke, such treatments are likely to provide considerable benenfits for affected individuals. Our study will investigate mechanisms underlying the death of brain cells in an animal model of stroke and in cells treated in culture. These studies will specifically focus on the role in cell death of alterations in mitochondria, a part of the cell that provides the energy needed for their normal function. The proposed investigations will identify molecular events that contribute to the mitochondrial dysfunction and examine the importance of these changes in brain tissue damage. The findings should contribute to the identication of new therapeutic approaches aimed at ameliorating the consequences of stroke.Read moreRead less