Structural And Functional Consequences Of LMNA Gene Mutations
Funder
National Health and Medical Research Council
Funding Amount
$357,904.00
Summary
Heart failure due to diseases of the heart muscle is a leading cause of illness and death in Australia. It has recently been discovered that mutations (changes in the DNA sequence) in genes in the heart are an important cause of heart muscle disease. In many cases, these gene mutations are passed from generation to generation in families. Mutations in the LMNA gene have been found to cause abnormalities of the heart s contraction and rhythm. The LMNA gene encodes two proteins, lamins A and C, th ....Heart failure due to diseases of the heart muscle is a leading cause of illness and death in Australia. It has recently been discovered that mutations (changes in the DNA sequence) in genes in the heart are an important cause of heart muscle disease. In many cases, these gene mutations are passed from generation to generation in families. Mutations in the LMNA gene have been found to cause abnormalities of the heart s contraction and rhythm. The LMNA gene encodes two proteins, lamins A and C, that are located in the muscle cell nucleus. The role of lamins A and C in the heart and the mechanism by which mutant proteins cause heart muscle disease are unknown. We propose to address these questions by studying a mouse model in which lamins A and C have been knocked out. We will also perform in vitro experiments to examine the effects of LMNA mutations that have been found in affected families. These studies will contribute to a better understanding of the causes of heart muscle disease and will ultimately lead to new approaches to the diagnosis and treatment of patients with heart failure and disturbances of heart rhythm.Read moreRead less
I investigate the regulation of blood flow in skeletal muscle and the control of muscle metabolism. In particular, my research focuses on the action of insulin on the microvasculature and the consequences of impairments of this function in obesity, hypert
Mechanisms Linking Insulin-mediated Muscle Capillary Recruitment And Glucose Uptake
Funder
National Health and Medical Research Council
Funding Amount
$315,990.00
Summary
A number of studies over recent years including our own have suggested that insulin acts in normal humans and animals to improve blood supply to muscle and that a contributing factor to Type 2 diabetes is an impaired ability of insulin to achieve this effect. Our key contribution to this field is the finding that insulin acts to alter blood flow in muscle to improve access for itself and nutrients such as glucose. This discovery of blood flow redistribution in muscle was made possible by newly d ....A number of studies over recent years including our own have suggested that insulin acts in normal humans and animals to improve blood supply to muscle and that a contributing factor to Type 2 diabetes is an impaired ability of insulin to achieve this effect. Our key contribution to this field is the finding that insulin acts to alter blood flow in muscle to improve access for itself and nutrients such as glucose. This discovery of blood flow redistribution in muscle was made possible by newly developed in-house methods. Using these methods we now wish to explore (a) the mechanism by which insulin mediates this effect and (b) when this effect of insulin to improve muscle blood flow is impaired in diabetes, how it might be recovered. We expect to find that insulin-mediated capillary recruitment in muscle results from a signal substance released from muscle that permeates nearby tissue reacting with the blood vessels to improve blood flow. It is also expected that new therapeutic approaches for enhancing insulin action in muscle and targeted at the blood vessels will be identified.Read moreRead less
Cyclic GMP Phosphodiesterase Inhibitors And Facilitation Of Insulin-mediated Capillary Recruitment In Muscle
Funder
National Health and Medical Research Council
Funding Amount
$220,500.00
Summary
It would now seem clear that insulin has a major stimulatory effect on blood flow within muscle to improve access for itself as well as nutrients such as glucose. When this haemodynamic effect of insulin is impaired insulin resistance in terms of glucose uptake by muscle results and there is the potential for type 2 diabetes to develop. Our key contribution has been the development of new techniques to make this observation possible and it would be fair to say that we are the world leaders in th ....It would now seem clear that insulin has a major stimulatory effect on blood flow within muscle to improve access for itself as well as nutrients such as glucose. When this haemodynamic effect of insulin is impaired insulin resistance in terms of glucose uptake by muscle results and there is the potential for type 2 diabetes to develop. Our key contribution has been the development of new techniques to make this observation possible and it would be fair to say that we are the world leaders in this field because of these techniques. Using these methods we now wish to develop new drugs for treating type 2 diabetes based on improving muscle capillary blood flow. The approach we will use is similar to that used previously by others for the treatment of erectile dysfunction with drugs targeted at a particular enzyme controlling the metabolism of a substance (cyclic GMP) which in turn regulates blood flow to the corpus cavernosum. In our case, the drugs will be targeted at another specific isoform of the same enzyme, cyclic GMP phosphodiesterase, located at control points in the skeletal muscle microvasculature. We expect to find that insulin-mediated capillary recruitment in muscle will be enhanced by such drugs. As a consequence, insulin resistance in muscle will be lessened.Read moreRead less
Coronary artery disease usually presents with chest pain resulting from cardiac muscle being starved of blood and oxygen due to narrowings in the coronary arteries supplying the heart muscle (myocardial ischaemia). The common test to detect this state is the electrocardiogram or ECG which often shows changes known as ST segment shifts. This project follows earlier work and will explain why the ST changes occur and also will determine how to maximize the information from the ECG so that clinician ....Coronary artery disease usually presents with chest pain resulting from cardiac muscle being starved of blood and oxygen due to narrowings in the coronary arteries supplying the heart muscle (myocardial ischaemia). The common test to detect this state is the electrocardiogram or ECG which often shows changes known as ST segment shifts. This project follows earlier work and will explain why the ST changes occur and also will determine how to maximize the information from the ECG so that clinicians are better able to predict the site, size and timing of the ischaemia from the ECG. The proposal will use detailed measurement of the electric field around the ischaemic region to build up the three dimensional electric field from which the explanation as to why the body surface patterns occur will be gleaned by computer modelling. This project will extend the field measurement back into the myocardium using intramyocardial electrodes with a spacing of 2 mm. This project will result in better analysis of the ECG in patients with chest pain, better practice in selecting patients for admission or early treatment and could result in substantial savings to the health system from reduced admissions, more appropriate investigation and treatment. A better diagnosis on one patient daily in Austarlia alone would be expected to save one million dollars in the year.Read moreRead less
Atherosclerosis (hardening of the arteries) is the principal cause of heart attack, stroke and blockage of blood flow to the lower limbs. However, to date none of the biological or synthetic grafts used to bypass the narrowed regions of arteries is ideal. We have shown that lengths of silicone tubing placed into the peritoneal cavity of rats or rabbits becomes covered within 2 weeks by a capsule of granulation tissue (smooth-muscle-like cells and collagen) and mesothelial (endothelial-like) cell ....Atherosclerosis (hardening of the arteries) is the principal cause of heart attack, stroke and blockage of blood flow to the lower limbs. However, to date none of the biological or synthetic grafts used to bypass the narrowed regions of arteries is ideal. We have shown that lengths of silicone tubing placed into the peritoneal cavity of rats or rabbits becomes covered within 2 weeks by a capsule of granulation tissue (smooth-muscle-like cells and collagen) and mesothelial (endothelial-like) cells. The silicone tubing can be removed and the tissue turned inside out such that the endothelial-like cells now line the inside of the tube of living tissue, which resembles a blood vessel. These artificial blood vessels will be grown in the peritoneal cavity of rabbits, then grafted into the right carotid artery to replace a length of removed vessel. Their long-term (3,6,9 and 12 months) patency, reactivity, tensile strength and resistance to clot development will be assessed. Their susceptibility to atherosclerotic plaque development and blockage (as compared with natural carotid artery) will be examined in rabbits fed a cholesterol-enriched diet. Changes in gene expression as the artificial artery progressively develops will be examined, as will the potential to genetically manipulate the artificial artery to improve its functioning. Finally, attempts will be made to grow the vessels entirely in vitro. This novel vascular graft may open new options in the field of arterial reconstructive surgery for replacing or bypassing diseased vessels or as an access vessel for haemodialysis patients with end stage renal failure. This study will also provide new information on the biology of cells found in the peritoneal cavity and their alternative pathways for differentiation.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