The Role Of Aquaporins In Cardiac Ischaemia And Reperfusion
Funder
National Health and Medical Research Council
Funding Amount
$412,670.00
Summary
We are studying the important clinical problem of why the heart doesn't work very well after it has been deprived of blood. This may occur during a heart attack due to coronary artery disease and during cardiac surgery when the heart is stopped. The problem affects children as well as adults undergoing surgery. The reason the heart doesn't work well is related to energy supply and tissue damage caused during the shortage of blood supply and the period soon after flow is restored. Until the heart ....We are studying the important clinical problem of why the heart doesn't work very well after it has been deprived of blood. This may occur during a heart attack due to coronary artery disease and during cardiac surgery when the heart is stopped. The problem affects children as well as adults undergoing surgery. The reason the heart doesn't work well is related to energy supply and tissue damage caused during the shortage of blood supply and the period soon after flow is restored. Until the heart recovers, inadequate pump function may cause low blood flow problems downstream in vital organs such as the brain and kidneys. Under the microscope, a common feature of affected hearts is swelling of the cells and of the energy producing parts called mitochondria. We have identified, for the first time, unique proteins that allow water to move into and around cells of the heart. These proteins are called 'aquaporins' and early results suggest they are involved in how mitochondria deal with a shortage of blood supply. Interestingly, aquaporins are also affected in diseases that affect muscle strength, and we are using what is known in these diseases to further study the role of aquaporins in the heart. Our experiments to will test heart function from the level of the cell, all the way up to the whole heart. To improve the power of our experiments, we are working with mice that lack the special water transport proteins, as a prelude to developing drug therapy for this important problem. By manipulating aquaporin levels or function, we plan to improve heart preservation during periods of no blood flow, and after surgery. This would importantly reduce the risks associated with heart attack and cardiac surgery by avoiding complications associated with poor pump function.Read moreRead less
Therapeutic Silencing Of Egr-1 By Novel Catalytic Oligodeoxynucleotides For The Treatment Of Acute Myocardial Infarction
Funder
National Health and Medical Research Council
Funding Amount
$384,353.00
Summary
Heart attack remains a major health problem. We have identified a gene in the heart which is turned on in the first few hours of a heart attack. We have shown in principle that switching this gene off using a novel synthetic drug, reduces heart attack size. Our project assesses the long term effects of this drug on the heart using state of the art imaging when the the drug is administered in a clinically relevant manner. This study may faciliate a new treatment approach for this condition.
The Role Of Diffuse Myocardial Fibrosis In Myocardial Stiffness
Funder
National Health and Medical Research Council
Funding Amount
$378,032.00
Summary
Collagen, a major component of scar, accumulates in some hearts and we may expect this to increase stiffness, threatening heart function. We have shown poor heart relaxation correlates with increased collagen on heart magnetic resonance imaging (MRI). We aim to establish a link between MRI findings and direct measures of heart stiffness, a link between degree of stiffness and amount of collagen and effects of anti-fibrotic therapy on heart collagen; aiding diagnosis, prognosis and outcome.
The Effect Of Ischaemia And Reperfusion On Sarcoplasmic Reticulum Calcium Handling In The Heart
Funder
National Health and Medical Research Council
Funding Amount
$236,208.00
Summary
Ischaemic heart disease is one of the most common causes of premature death in our society. Ischaemia occurs when the blood flow to the heart is obstructed so that oxygen cannot get to the muscle cells and metabolic waste products cannot be washed away. During ischaemia the concentration of free calcium within a cardiac muscle cell increases, and when blood flow is returned to the muscle this calcium concentration can increase further to very high levels. It is this change in calcium that is res ....Ischaemic heart disease is one of the most common causes of premature death in our society. Ischaemia occurs when the blood flow to the heart is obstructed so that oxygen cannot get to the muscle cells and metabolic waste products cannot be washed away. During ischaemia the concentration of free calcium within a cardiac muscle cell increases, and when blood flow is returned to the muscle this calcium concentration can increase further to very high levels. It is this change in calcium that is responsible for the reduced muscle force and abnormal cardiac rhythm that are the main cause of death. Cardiac muscle cells contain an intracellular compartment called the sarcoplasmic reticulum (SR). Under normal conditions the SR stores large amounts of calcium in order to maintain a low concentration of calcium free within the cell. However, even in a resting cell, calcium can escape from the SR through channels in SR membrane. We are using a state-of-the-art microscope to visualize these tiny packets of calcium, termed calcium sparks, as they travel through the SR membrane. If the number of calcium sparks increases, the amount of calcium being released from the SR also increases. We are studying what happens to calcium sparks, and therefore SR calcium release, during ischaemic heart disease. We are also examining the effect of ischaemic heart disease on the concentration of calcium within the SR and the activity of the transporters that pump calcium back into the SR. We hope to show that a change in the way the SR regulates calcium contributes to ischaemic damage. Understanding how changes in SR function alter muscle force and cardiac rhythm will help in the development of drugs to protect against ischaemic damage.Read moreRead less
I am a cardiac pharmacologist investigating new therapies for the precursors of, and preventing their transition to, heart failure. My core activities focus on factors that control cardiac hypertrophy and ventricular function, in both the absence and pres
Regulation Of Mammalian Heart Regeneration By The MiR-15 Family.
Funder
National Health and Medical Research Council
Funding Amount
$435,859.00
Summary
The inability of the adult heart to regenerate following a heart attack is a major contributor to the burden of heart disease in the developed world. We have recently discovered that, for a brief period after birth, the newborn heart can completely regenerate itself following injury. Understanding how and why the heart loses this remarkable capacity for regeneration shortly after birth may hold the key for developing cardiac regenerative therapies.
Reduced Ischaemic Tolerance In The Aged Myocardium: The Role Of Adenosine And Adenosine Receptors
Funder
National Health and Medical Research Council
Funding Amount
$470,250.00
Summary
Despite a decline in deaths rates due to heart disease over the last decade, cardiovascular disease remains the single greatest cause of premature death in individuals over 65 years of age. It accounts for a major and increasing portion of health care costs. Coronary artery disease affects 50% of those older than 65, and with the ageing of our population it is estimated that the elderly population will nearly double from 13-14% to 25% over the next 30 years. Unfortunately, it appears that the ag ....Despite a decline in deaths rates due to heart disease over the last decade, cardiovascular disease remains the single greatest cause of premature death in individuals over 65 years of age. It accounts for a major and increasing portion of health care costs. Coronary artery disease affects 50% of those older than 65, and with the ageing of our population it is estimated that the elderly population will nearly double from 13-14% to 25% over the next 30 years. Unfortunately, it appears that the aged heart is less resistant to disease and injury, contributing to the increase in mortality with ageing. The reasons are not known. This research project will attempt to identify molecular changes which occur in the heart during ageing which may lead to a decline in ability to withstand disease and injury. The research will specifically examine the possibility that a key protective response, known as the adenosine receptor system, is somehow impaired or abnormal in the cells of the aged heart. If it is found that this process is impaired, the research will attempt to rectify this abnormality using new genetic therapy techniques to switch on the heart's own intrinsic defense mechanisms. This may ultimately open up new avenues for specific therapeutic approaches to treatment of ischaemic heart disease in the elderly.Read moreRead less
Structural And Functional Alterations Of Sarcomeric Proteins In Reperfused Myocardium
Funder
National Health and Medical Research Council
Funding Amount
$271,786.00
Summary
Coronary artery disease remains the major cause of mortality for the adult population in our society. Despite the advances of coronary artery bypass surgery and medical treatment for reperfusion of occluded coronary arteries, the problem of impaired pump function of the heart remains a major obstacle. Although blood flow can be restored to the jeopardised heart muscle by either clot dissolving drugs, balloon angioplasty, or coronary artery surgery, the heart muscle may not regain pump function f ....Coronary artery disease remains the major cause of mortality for the adult population in our society. Despite the advances of coronary artery bypass surgery and medical treatment for reperfusion of occluded coronary arteries, the problem of impaired pump function of the heart remains a major obstacle. Although blood flow can be restored to the jeopardised heart muscle by either clot dissolving drugs, balloon angioplasty, or coronary artery surgery, the heart muscle may not regain pump function for days to weeks after the event. This delayed recovery of pump function, known as myocardial stunning, can lead to heart failure and slow down a patient's recovery from heart surgery or heart attack. The cause of this myocardial stunning is unknown. We suggest that stunning results from damage to essential proteins in the contractile apparatus of the heart, which requires a prolonged time period for repair. This project aims to identify the site and extent of protein damage occurring in the heart following interruption and subsequent restoration of cardiac blood flow. In concert with this, we seek to determine the mechanism of protein damage. The findings of this project should allow us to subsequently investigate new treatment approaches for acute pump dysfunction in patients with ischaemic heart disease.Read moreRead less
The Role Of C-reactive Protein (CRP) In Localising Inflammation To Misfolded Proteins And “stressed” Cells: A Basis For The Development Of New Anti-inflammatory Reagents?
Funder
National Health and Medical Research Council
Funding Amount
$723,488.00
Summary
Many diseases are exacerbated by inflammatory reactions. We describe how a protein circulating in the blood is a major driver of inflammatory reactions and how it is transformed from an inactive state to an active, highly pro-inflammatory state. Our project aims to understand how this transformation occurs at the molecular level, and to develop diagnostic techniques and innovative drugs to treat diseases such as heart attack, Alzheimer’s disease and other inflammatory diseases.