Effects Of The Atrial Natriuretic Factor Enhancer And The 5'HS4 Insulator On The Probability Of Gene Expression.
Funder
National Health and Medical Research Council
Funding Amount
$534,628.00
Summary
Complex organisms contain many different types of cells, which can have completely different appearances and functions. All of these cells contain the same genes; the differences between them are achieved by the selective use of the genes. The means by which the selective use of genes is accomplished is a key to understanding how complex organisms develop, and how that development goes awry in cancer, heart disease, and other common disorders. A very large body of evidence indicates that gene re ....Complex organisms contain many different types of cells, which can have completely different appearances and functions. All of these cells contain the same genes; the differences between them are achieved by the selective use of the genes. The means by which the selective use of genes is accomplished is a key to understanding how complex organisms develop, and how that development goes awry in cancer, heart disease, and other common disorders. A very large body of evidence indicates that gene regulation is accomplished by the interaction of protein factors with segments of DNA flanking the gene. One hypothesis underlying our work is that the flanking DNA elements act primarily to increase the probability that a gene will be active rather than silent. We will ask if removing a known regulatory element from the gene for Atrial Natriuretic Factor (ANF) in mice reduces the likelihood of ANF being expressed by heart cells when the heart is stressed. This experiment will also shed new light on an extremely common disease state in humans (cardiac hypertrophy). In a second experiment, we will use a new experimental system we have developed to ask if a gene regulatory element is able to dial up the amount of expression from a gene, as well as to switch the gene on. Our previous work suggested this was not the case, but we wish to conduct a more rigorous test. Another hypothesis is that no DNA element is able to completely shield a transferred gene from the regulatory elements surrounding it. Accordingly, we will test a DNA element that has been proposed to insulate any gene from all influences of surrounding genes, and ask if it is able to create an autonomously expressing gene at any site within the genome. Because they deal with functions that are common to all genes, these experiments will provide information that should be applicable to a broad array of efforts to manipulate gene expression.Read moreRead less
Effects Of Atrial Natriuretic Peptide On The Sarcolemmal Na-K Pump In Rabbit Myocytes
Funder
National Health and Medical Research Council
Funding Amount
$225,500.00
Summary
The sodium pump transports sodium ions across cell membranes from the inside of cells to the outside. This maintains the concentration of sodium more than ten-fold lower on the inside than the outside. This transmembrane concentration gradient is essential for normal cell function. It is well established that the sodium pump is regulated by a variety of hormones. In a pilot study we have demonstrated that a hormone secreted by the heart, atrial natriuretic peptide, stimulates the sodium pump in ....The sodium pump transports sodium ions across cell membranes from the inside of cells to the outside. This maintains the concentration of sodium more than ten-fold lower on the inside than the outside. This transmembrane concentration gradient is essential for normal cell function. It is well established that the sodium pump is regulated by a variety of hormones. In a pilot study we have demonstrated that a hormone secreted by the heart, atrial natriuretic peptide, stimulates the sodium pump in single heart cells. This has not been reported previously. This study will examine the cellular mechanisms that mediate the stimulation of the sodium pump by atrial natriuretic peptide. A study on the effect of atrial natriuretic peptide on the regulation of sodium in heart cells is particularly important from the perspective of heart failure, a condition characterised by an inability of the heart to pump a sufficient amount of blood. While the underlying causes of heart failure vary widely activation of several hormone systems is a common feature regardless of the aetiology. It has already been well established in clinical practice that interfering with hormone activation by drugs improves symptoms as well as survival. Drugs have recently been developed that can increase levels of atrial natriuretic peptide. Since raised levels of sodium may contribute to important heart cell abnormalities in heart failure the effect of atrial natriuretic peptide on sodium export from the cells by the pump may have important implications for treatment of this serious and common condition.Read moreRead less
Atrial Electrical Remodeling Due To Chronic Stretch: Defining The Substrate For Atrial Fibrillation
Funder
National Health and Medical Research Council
Funding Amount
$428,250.00
Summary
Background: Cardiac failure is a common heart disorder in which the pumping function of the heart is significantly weakened. Mitral regurgitation is a common condition where there is a leakage of blood from the left ventricle (lower heart chamber) back into the left atrium (upper heart chamber) during normal cardiac contraction. This puts a strain on the heart and may cause heart failure. Atrial septal defect is a common form of congenital heart disease which may not be diagnosed until adulthood ....Background: Cardiac failure is a common heart disorder in which the pumping function of the heart is significantly weakened. Mitral regurgitation is a common condition where there is a leakage of blood from the left ventricle (lower heart chamber) back into the left atrium (upper heart chamber) during normal cardiac contraction. This puts a strain on the heart and may cause heart failure. Atrial septal defect is a common form of congenital heart disease which may not be diagnosed until adulthood. There are several forms but the basic problem is leakage of blood from the left atrium into the right atrium .This also puts a strain on the heart and can cause heart failure. All 3 conditions are associated with a significantly increased risk of atrial fibrillation (AF). This abnormal fast irregular cardiac rhythm makes the pumping of the heart inefficient. People with AF may feel short of breath, tired, or develop palpitations. AF is an important cause of stroke and premature death and is the most common heart rhythm disturbance occurring in upto 10% of the over 70 age group. Even after repair of the leaky valve or atrial septal defect there is still a high risk of developing this rhythm. Purpose of the study: This study will try to understand why patients with these conditions are at risk of developing atrial fibrillation, and why this risk might persist after surgical correction when this is possible (mitral regurgitation and atrial septal defect). The study will utilise sophisticated new mapping techniques to gain original insights into the mechanism of this very common and as yet poorly understood heart rhythm disturbance. The study has the potential to determine the cause of atrial fibrillation in these patient groups and as such represent a quantum advance in our understanding of he mechanism of atrial fibrillation. It would be expected to form a foundation on which development of curative and preventative approaches may be based.Read moreRead less
Analysis Of Atrial Electrical Remodelling In Patients With Paroxysmal And Persistent Atrial Fibrillation
Funder
National Health and Medical Research Council
Funding Amount
$127,516.00
Summary
I am a cardiologist undertaking further training in the management of electrical abnormalities of the heart. My research will focus on the mechanisms responsible for atrial fibrillation, the most common serious heart rhythm disorder. I intend to do this by examining the nature of the electrical activity in patients with atrial fibrillation and comparing this to electrical activity in patients without this disorder, who are undergoing treatment procedures for their electrical disorder.