FOXO Proteins And Protection From Cardiac Ischaemic Injury
Funder
National Health and Medical Research Council
Funding Amount
$354,375.00
Summary
Reduced blood supply to the heart can initiate a heart attack that results in damage to the heart muscle. Loss of muscle tissue under these conditions initiates pathological growth of the heart and can eventually lead to the development of heart failure, a major cause of death and disability in western countries. Treatment with growth factors can prevent the acute damage and loss of cells, but these cause detrimental effects on other tissues. For these reasons, it is necessary to establish ways ....Reduced blood supply to the heart can initiate a heart attack that results in damage to the heart muscle. Loss of muscle tissue under these conditions initiates pathological growth of the heart and can eventually lead to the development of heart failure, a major cause of death and disability in western countries. Treatment with growth factors can prevent the acute damage and loss of cells, but these cause detrimental effects on other tissues. For these reasons, it is necessary to establish ways to activate protective pathways in the heart without causing unwanted effects on other tissues. To this end, we have identified for the first time in the heart members of a newly described family of gene regulators that can cause cell death by increasing expression of cytotoxic factors. We showed that these FKHRor FOXO family members are regulated in the heart and that they are active in generating cytotoxic factors. We now plan to establish whether FOXO proteins are involved in causing cell death during heart attack and whether manipulating their activities can be cardioprotective.Read moreRead less
MYOCARDIAL NEOVASCULARIZATION FOR ISCHEMIC HEART DISEASE USING BONE MARROW-DERIVED ANGIOBLASTS
Funder
National Health and Medical Research Council
Funding Amount
$577,400.00
Summary
Congestive heart failure remains a major public health problem. In Western societies heart failure is primarily the consequence of a previous myocardial infarction. We have recently identified certain cells in the bone marrow of adult humans that can cause new blood vessel development in the heart after infarction, protecting the heart muscle cells against death and preventing heart failure. Since the cardiovascular diseases that are most likely to benefit from treatments utilizing adult bone ma ....Congestive heart failure remains a major public health problem. In Western societies heart failure is primarily the consequence of a previous myocardial infarction. We have recently identified certain cells in the bone marrow of adult humans that can cause new blood vessel development in the heart after infarction, protecting the heart muscle cells against death and preventing heart failure. Since the cardiovascular diseases that are most likely to benefit from treatments utilizing adult bone marrow-derived endothelial progenitors, or angioblasts, predominantly affect aging individuals, critical questions that must be addressed are whether advanced age and-or progression of cardiovascular disease reduce the total numbers and-or the functional activity of such cells. In the current proposal we will investigate the relationship between increasing age or progression of ischemic heart disease and changes in the number and in vivo biologic properties of human angioblasts. Patients at various ages and stage of cardiovascular disease will be studied. Angioblast numbers will be quantitated in freshly obtained bone marrow cells. The ability of purified angioblasts to be targeted to the ischemic heart will be studied by labeling the angioblasts with a radioactive tracer and measuring tracer uptake in the heart at various time points after intravenous infusion of the cells. Finally, angioblast functional capacity will be evaluated using standard measurements of heart function before and at various time points after reinfusion of cells into the donor. In Aims 2 and 3 of this proposal we will focus our investigations on the potential use of angioblast therapy for reversal of established chronic heart failure in our animal models. Specifically, we will investigate whether induction of neovascularization results in cardiomyocyte regeneration and explore novel strategies to augment heart muscle regeneration by increasing angioblast trafficking to the damaged myocardium .Read moreRead less
Primary Cardiac Hypertrophy - A Functional Genetic Approach To Investigate Cellular Mechanisms Of Metabolic Remodelling
Funder
National Health and Medical Research Council
Funding Amount
$226,692.00
Summary
Population studies have recently shown that enlargement of the heart, even when blood pressure is normal, is a risk factor which can lead to cardiovascular complications. Very little is known about the alterations in heart cell structure and function which occur in cardiac enlargement not complicated by high blood pressure. It is possible that specific metabolic abnormalities underlie this condition. The goal of this study is to use a newly developed genetically manipulated experimental animal m ....Population studies have recently shown that enlargement of the heart, even when blood pressure is normal, is a risk factor which can lead to cardiovascular complications. Very little is known about the alterations in heart cell structure and function which occur in cardiac enlargement not complicated by high blood pressure. It is possible that specific metabolic abnormalities underlie this condition. The goal of this study is to use a newly developed genetically manipulated experimental animal model to study the function of single heart cells. In this model one of the glucose transporters has been deleted. Our goal is to compare heart function in this genetic model with heart function in diabetes. Cells are isolated from hearts using enzyme treatments and investigated microscopically to determine if there are subcellular structural alterations. Functional studies are performed on individual viable cells using a combination of electrical recording techniques and fluorescence imaging methods. The experimental aim is to assess whether there is disruption of sodium, calcium or pH regulation associated with cardiac enlargement associated with metabolic abnormalities. This research will assist in identifying appropriate therapeutic strategies for intervention in the treatment or prevention of conditions associated with cardiac enlargement.Read moreRead less
Linking Early Heart Growth Stress And Adult Cardiopathology: A New Role For Autophagy
Funder
National Health and Medical Research Council
Funding Amount
$524,013.00
Summary
An enlarged heart at maturity is a major risk factor. The goal of this project is to understand how cardiac growth abnormality in the neonate contributes to adult growth pathology. We have recently discovered that a type of stress-triggered cell death (autophagy) is increased in rodent neonatal hearts which later become enlarged, and that this cell death is regulated by the hormone angiotensin II. We will study the mechanisms involved to identify intervention opportunities to normalize growth.
ISOLATION, EXPANSION AND CHARACTERIZATION OF HUMAN CARDIAC PROGENITOR CELLS.
Funder
National Health and Medical Research Council
Funding Amount
$573,993.00
Summary
At present there are limited treatment options for cardiac diseases such as heart failure. Stem cell research offers the opportunity to find new treatments for myocardial disease. We aim to isolate and expand cardiac cells derived from human embryonic stem cells and use them to simulate heart disease in the laboratory improve our understanding of cardiac disease. We hope that in future these cells will enable the discovery of drugs that alleviate the suffering associated with the disease.
Clinical trials and experimental investigations have demonstrated that a diet rich in fish oil, containing high levels of omega 3 fatty acids, provides protection against arrhythmias and sudden cardiac death associated with heart failure. Surprisingly little is known about how these dietary omega 3 lipids alter the electrical and mechanical function of cardiac muscle cells when incorporated into the membrane of these cells. The goal of this study is to examine how experimental omega 3 diet treat ....Clinical trials and experimental investigations have demonstrated that a diet rich in fish oil, containing high levels of omega 3 fatty acids, provides protection against arrhythmias and sudden cardiac death associated with heart failure. Surprisingly little is known about how these dietary omega 3 lipids alter the electrical and mechanical function of cardiac muscle cells when incorporated into the membrane of these cells. The goal of this study is to examine how experimental omega 3 diet treatment can modify the heart muscle cell structure and function. In particular we will determine which cellular mechanisms may be important in conferring selective benefit of dietary intervention on pre-failing heart function. For this study we will use mice which exhibit signs of heart failure induced by hormone overproduction (angiotensin II) and by elevation of blood pressure (by surgical constriction). Mice will be fed omega-3 and omega-6 diets and experiments to investigate cardiac muscle cell structure and function will be carried out using a variety of electrical recording, microscopic and molecular biology techniques. Diet-induced changes in the capacity of the heart cells to regulate calcium will be investigated using cells loaded with fluroescent indicators. Single cell electrical recording techniques (patch clamp) will also be used in combination with ECG measurement to evaluate how arrhythmic activity arising from electrically and mechanically unstable cells can be suppressed by omega-3 diet intervention. Finally we will take the first step towards validating the rodent experimental findings in a clinical setting with measurements of calcium transporters and channel expression in human specimens from cardiac surgery patients.Read moreRead less
Mechanisms Regulating Ribosomal Gene Transcription During Cardiac Hypertrophy
Funder
National Health and Medical Research Council
Funding Amount
$436,540.00
Summary
After birth the muscle cells of the human heart stop dividing. Subsequent growth of the heart is achieved by increasing the size of preexisting muscle cells. This process is referred to as hypertrophic growth and accounts for the difference in size between the juvenile and adult human heart. However later on in life, particularly during cardiovascular disease states such as high blood pressure, the adult heart may grow above and beyond that normally expected. This uncontrolled growth, results ev ....After birth the muscle cells of the human heart stop dividing. Subsequent growth of the heart is achieved by increasing the size of preexisting muscle cells. This process is referred to as hypertrophic growth and accounts for the difference in size between the juvenile and adult human heart. However later on in life, particularly during cardiovascular disease states such as high blood pressure, the adult heart may grow above and beyond that normally expected. This uncontrolled growth, results eventually in a sick heart which is no longer able to function properly. Such inappropriate growth of the heart is a component of many human cardiovascular disease states and contributes significantly to human morbidity and mortality. Regardless of the cause, hypertrophic growth of the heart results from increased protein synthesis. This is controlled by increased synthesis of ribosomes, the machinery responsible for making proteins. During the course of our studies investigating the regulation of heart muscle cell hypertrophy we have demonstrated that changes in the activity of a protein termed UBF, which is involved in regulating synthesis of ribosomes, correlates with the rate of hypertrophic growth. We have also demonstrated that if we artificially increase the amount of UBF protein in heart muscle cells we can stimulate hypertrophy. These finding indicate that alterations in the amount or activity of UBF may link hypertrophic stimuli to increased growth of the heart. The work described in this study proposes to investigate the signals and pathways which regulate the amount and activity of the UBF protein during hypertrophic growth of heart muscle cells. We hope by understanding the mechanisms by which the heart grows we will be able to design rational therapeutic regimens to combat the abnormal growth of the heart that often accompanies human cardiovascular disease states such as high blood pressure.Read moreRead less