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
Adenosine A1 And A3 Receptor Mediated Cardioprotection In Ischaemic Myocardium
Funder
National Health and Medical Research Council
Funding Amount
$265,698.00
Summary
Damage to the heart from coronary vascular disease causes significant morbidity and mortality in Australia. Indeed, ischaemic injury represents the single greatest cause of premature death. Moreover, due to the increasing age of our population the problem is growing - coronary artery disease affects 50% of those older than 65, contributing to an increased incidence of angina pectoris, myocardial infarction, arrhythmia, congestive heart failure, and sudden death. Protective strategies have been, ....Damage to the heart from coronary vascular disease causes significant morbidity and mortality in Australia. Indeed, ischaemic injury represents the single greatest cause of premature death. Moreover, due to the increasing age of our population the problem is growing - coronary artery disease affects 50% of those older than 65, contributing to an increased incidence of angina pectoris, myocardial infarction, arrhythmia, congestive heart failure, and sudden death. Protective strategies have been, and continue to be, developed to reduce the extent of tissue damage and minimise prolonged reductions in heart function. The success of these interventions has been mixed. This research project takes the novel approach of identifying the true roles of two receptors present in the heart (the adenosine A1 and A3 receptors) which may play a crucial role in enhancing tolerance of the heart to disease and injury. We currently do not fully understand the roles of these receptors, although preliminary findings suggest they can exert powerful protective effects during disease conditions. From a fundamental viewpoint, identifying the roles of these two receptors will significantly advance our understanding of the mechanisms of injury and protection in the heart. From a therapeutic viewpoint, this study will take us closer to the potential use of adenosine receptor-based therapy in protecting the heart from ischaemic injury.Read moreRead less
The Importance Of P38 MAPK Signalling In Aging-Related Ischaemic Intolerance And Failed Cardioprotection
Funder
National Health and Medical Research Council
Funding Amount
$496,302.00
Summary
Ischaemic heart disease is the leading cause of death in Australia, and will rise in coming years with the aging of our population. Our research shows aged hearts become less resistant to damage during ischaemia-heart attack, and insensitive to normally beneficial therapies. This project will identify molecular changes responsible for these changes. By understanding how age impairs the hearts defences, it may be possible to improve therapy of ischaemic heart disease in older patients.
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
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.
Troponin Rise After Emergency Orthopaedic-geriatric Surgery Randomised To Standard Care Versus Cardiology Care
Funder
National Health and Medical Research Council
Funding Amount
$87,193.00
Summary
This project will determine whether older patients who undergo emergency orthopaedic surgery who sustain cardiac injury (detected by means of a blood test called Troponin I) benefit from cardiology care as opposed to standard care. Troponin I is used to detect heart injury and can be elevated after surgery even if the patient is asymptomatic. Patients with a troponin elevation have a higher risk of death at 1 year. It is proposed that cardiology care and follow up might improve outcomes.
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