Role Of The T-box Transcription Factors, Tbx5 And Tbx20, In Cardiac Development And Congenital Heart Disease
Funder
National Health and Medical Research Council
Funding Amount
$345,000.00
Summary
Structural defects in the heart are present in approximately 1 in 100 live births, and 1 in 10 still births in developed countries. Some 8% of deaths in the first year of life are caused by such abnormalities. While some defects can be repaired in childhood many go undetected and compound in later years leading to sudden death or compromised quality of life. Virtually all inherited heart defects for which the underlying genetic alteration is known are caused by mutations in genes controlling dev ....Structural defects in the heart are present in approximately 1 in 100 live births, and 1 in 10 still births in developed countries. Some 8% of deaths in the first year of life are caused by such abnormalities. While some defects can be repaired in childhood many go undetected and compound in later years leading to sudden death or compromised quality of life. Virtually all inherited heart defects for which the underlying genetic alteration is known are caused by mutations in genes controlling development of the heart in the embryo. Examples are Tbx5, a member of the T-box family of transcription factor genes mutated in Holt Oram syndrome, and Nkx2-5, a homeodomain transcription factor gene mutated in families with hole in the heart and cardiac electrical defects. We propose to investigate the involvement of a new member of the T-box gene family, Tbx20, in cardiac development and disease, and to compare and contrast its function with that of Tbx5. The Tbx5 and Tbx20 proteins interact directly with Nkx2-5 to stimulate transcription of cardiac genes, making Tbx20 a good candidate for involvement in inherited disease. We will use gene targeting technology to delete the Tbx20 gene in mice, and will analyse heart anatomy, gene expression and function to determine the effect of its loss. We will also investigate how Tbx20 interacts with other cardiac regulatory pathways, by crossing Tbx20 mutant mice with mice deficient for Nkx2-5 and Tbx5, strains that show heart abnormalities similar to those found in human patients. Microarray technology, which examines gene expression on a whole genome scale, will also be used to identify genes that are regulated by these transcription factors. Finally, we will search for mutations in the Tbx20 gene in human patients that have inherited heart abnormalities. In doing so we may improve our understanding of disease causation and predisposition thereby identifying patients at risk and providing improved genetic counselling and diagnosis.Read moreRead less
Spinal cord cysts can develop after spinal injury or in association with tumours or congenital abnormalities of the spine. These cysts often cause pain and paralysis. Treatment is often ineffective, partly because the source of the cyst fluid is unknown. We are investigating the origin of this fluid using animal models of spinal cord cysts, computer simulations, and MRI studies of patients with spinal cord cysts. Understanding the origin of cyst fluid will help us to develop improved treatment.
Heartbeats are considered to arise through specialised pacemaker cells establishing rhythmically generated (i.e. pacemaker) action potentials, which then trigger propagating action potentials in heart muscle causing contraction and pumping of blood. This research proposal aims to challenge the physical model that is used to describe this pacemaker process and resultant heart conduction. Our reasons for doing this derive from our discovery of an alternative pacemaker-conduction mechanism, which w ....Heartbeats are considered to arise through specialised pacemaker cells establishing rhythmically generated (i.e. pacemaker) action potentials, which then trigger propagating action potentials in heart muscle causing contraction and pumping of blood. This research proposal aims to challenge the physical model that is used to describe this pacemaker process and resultant heart conduction. Our reasons for doing this derive from our discovery of an alternative pacemaker-conduction mechanism, which we have shown to operate in various smooth muscles. This mechanism, termed store-based pacemaking, is entirely different to the currently held cardiac model but could readily achieve the same outcome. We will investigate the hypotheses that this pacemaker mechanism is also fundamental to mammalian heart pacemaking and conduction. Positive support for our hypotheses, as indicated by our findings on amphibian hearts and from pilot findings, may severely challenge the present model for cardiac pacemaking. Such an outcome will have major ramifications on present interpretation of cardiac function in health and disease and will be particularly important to interpretation of disorders associated with cardiac arrhythmias and heart conduction.Read moreRead less
Noncontact Biventricular Mapping And Intramural Ablation In A Chronic Ovine Model Of Septal Ventricular Tachycardia
Funder
National Health and Medical Research Council
Funding Amount
$519,279.00
Summary
Ventricular tachycardia (VT), an abnormal rhythm originating from the bottom portion of the heart is the major cause of sudden death in the community. Medications are not reliably effective. Expensive (costing about $40,000 every 5 years) implanted defibrillators are very effective in terminating VT, but frequently require painful shocks. Patients who require frequent treatment from their defibrillators are considered for mapping and ablation. About half of the patients with VT have the arrhythm ....Ventricular tachycardia (VT), an abnormal rhythm originating from the bottom portion of the heart is the major cause of sudden death in the community. Medications are not reliably effective. Expensive (costing about $40,000 every 5 years) implanted defibrillators are very effective in terminating VT, but frequently require painful shocks. Patients who require frequent treatment from their defibrillators are considered for mapping and ablation. About half of the patients with VT have the arrhythmia originating from the septum (heart muscle separating the two bottom portions of the heart). This area of the heart is difficult to map from an electrical point of view. A new type of mapping system called the Ensite 3000 system enables acquisition of 3,300 virtual electrical signals from within a heart chamber using an electrode array that does not have to be in direct contact with the heart muscle surface. Our evaluation of the Ensite system in one chamber of the heart has found it to be very good in identifying areas of abnormal electrical activity. It is possible that simultaneous mapping from both sides of the septum using Ensite might be useful in mapping VT originating from the septum. Destruction of the abnormal area, once identified, is generally done using a catheter, but is limited by its ability to destroy targets deep in the heart tissue. We have designed and developed a catheter that is equipped with a needle at its tip that can create deeper lesions. In this study we will be evaluating mapping using the Ensite electrodes in both ventricles in a chronic sheep model with VT originating from the septum. The Ensite mapping will be validated with detailed contact (conventional) mapping. The prototype catheter will be used to destroy the site of origin of VT, once identified. This study should enable more effective treatment of patients with VT and improve their quality of life.Read moreRead less
Enkephalin Metabolism In Cardiac Ischemia, Heart Failure And Cardiac Surgery
Funder
National Health and Medical Research Council
Funding Amount
$327,037.00
Summary
It has recently been discovered in animal studies that heart muscle can make its own opioid proteins. Previously, it was thought that only nerves made and released opioids. We have recently found that a class of opioids called enkephalins are made and then depleted from the heart during the stress of oxygen and nutrient deprivation. Enkephalins have been found to have potent metabolic effects on the heart. Previous work has shown that opioids can protect the heart against injury incurred during ....It has recently been discovered in animal studies that heart muscle can make its own opioid proteins. Previously, it was thought that only nerves made and released opioids. We have recently found that a class of opioids called enkephalins are made and then depleted from the heart during the stress of oxygen and nutrient deprivation. Enkephalins have been found to have potent metabolic effects on the heart. Previous work has shown that opioids can protect the heart against injury incurred during disease that restricts energy and oxygen supply to the blood vessels and heart. We wish to demonstrate this for the first time in human heart, and we will explore whether the production of enkephalins is altered by the stresses of cardiac surgery and heart failure. Understanding how the human heart attempts to protect itself in disease and how enkephalins work under these conditions, may prove valuable in the development of new drug therapy with synthetic drugs which mimic the action of enkephalins for heart protection during cardiac surgery, heart transplantation and ischemic heart disease. We will test whether specific enkephalins may be used to improve donor heart viability for transplantation by improving the duration and quality of preservation during storage. Understanding what happens to enkephalin production and metabolism in the failing hearts of patients may allow us to find new therapeutic targets in heart failure.Read moreRead less
The Role Of The Cytoskeleton In Communication Between The L-type Ca2+ Channel And The Mitochondria In Cardiac Pathology
Funder
National Health and Medical Research Council
Funding Amount
$542,890.00
Summary
The L-type calcium channel is a protein in the membrane of heart muscle cells responsible for maintaining normal rhythm and contraction. We have shown that the channel can also regulate the function of the energy producing part of the cell (mitochondria). This occurs with the assistance of proteins that maintain cell architecture. We will test whether this association is altered in human disease where the cell architecture is disrupted to determine the mechanisms for poor energy supply.
TRANSCRIPTIONAL AND FUNCTIONAL CONSEQUENCES OF STAT3 ACTIVATION IN THE HEART
Funder
National Health and Medical Research Council
Funding Amount
$413,694.00
Summary
Recent statistics show that the disease known commonly as heart failure accounts for about 3000 deaths each year in Australia. Worldwide, a staggering 10 million people are thought to currently suffer from heart failure, with this number continuing to rise despite decreasing numbers of people suffering from other forms of heart and blood vessel disease. What causes a healthy heart to fail remains unclear, although in some circumstances failure is known to be initiated by genetic factors, viral f ....Recent statistics show that the disease known commonly as heart failure accounts for about 3000 deaths each year in Australia. Worldwide, a staggering 10 million people are thought to currently suffer from heart failure, with this number continuing to rise despite decreasing numbers of people suffering from other forms of heart and blood vessel disease. What causes a healthy heart to fail remains unclear, although in some circumstances failure is known to be initiated by genetic factors, viral factors, alcoholism, high blood pressure, or when the heart is damaged in a heart attack. We are interested in the molecular mechanisms that underlie the progression of the normal heart to failure. In 2003 we reported on altered signalling pathways in the failing human heart, and noted the increased phosphorylation of a spliceform of the transcription factor STAT3 in patients with heart failure. In this project, we will evaluate a larger group of heart failure patients for changes in phosphorylation of their STAT3 proteins. We will also increase the expression of an activated form of the STAT3 proteins in rat heart cells, and check whether there are accompanying changes in gene expression profiles that indicate a potential role in heart failure, or whether these cells are now predisposed to die. This will be extended with the use of transgenic animals (mice) engineered to overexpress activated STAT3 proteins. Again, we will focus on gene expression profiles. We will also evaluate whether the hearts of these animals are more likely to fail, either as the animals age, or when external stresses are experienced. With this information, we will be able to state whether STAT3 is a contributor to heart failure, and therefore whether it is an attractive target for future therapies aimed at reducing the morbidity and mortality of heart failure worldwide.Read moreRead less
Genetic Control Of Body Patterning: Intersection Of Transcriptional And Signalling Activity In Head Formation
Funder
National Health and Medical Research Council
Funding Amount
$579,932.00
Summary
A most critical step in embryonic development is the assembly of the different tissue components into a three-dimensional structure in order to build a major body part of the foetus. The objective of our research is to understand how the mechanisms that control genetic activity and cell-to-cell signalling may cooperate in the formation of the head and face of the embryo. The outcome will focus future clinical investigations to the most relevant genetic determinants of craniofacial defects.
Investigation Of Sudden Cardiac Death In The Young
Funder
National Health and Medical Research Council
Funding Amount
$682,823.00
Summary
Sudden cardiac death is a major tragedy in young people. In approximately one third of such cases, no cause of death is found at autopsy. This study will investigate the causes of sudden cardiac death in the young, with a specific emphasis on the underlying genetic causes of sudden unexplained death. This information will be used for screening surviving family relatives, thereby improving both diagnostic and treatment-prevention opportunities and reducing sudden cardiac death in our community.
Roles Of Interleukins, Chemokines And Circulating Cells In Cardiac Fibrosis
Funder
National Health and Medical Research Council
Funding Amount
$434,134.00
Summary
Cardiac fibrosis is a disease of the heart in which large amounts of collagen are deposited within the heart tissue. This leads to poor heart function and may also lead to sudden death due to arrhythmias (abnormal electrical pulses). This study sets out to define the role of substances called interleukins and special circulating cells called lymphocytes, macrophages and progenitor cells in the development of cardiac fibrosis.