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
Regulation Of Cardiac Hypertrophy A At The Level Of Ribosome Biogenesis
Funder
National Health and Medical Research Council
Funding Amount
$634,587.00
Summary
A major feature of cardiac hypertrophy (enlarged heart) is accelerated cell growth and protein synthesis. This results from increased synthesis of ribosomes (the protein synthetic machinery). This study will examine a factor termed UBF whose activity is critical for the regulation of ribosome synthesis. Understanding the mechanisms controlling UBF function will provide new avenues in which to develop therapeutics to combat hypertrophic heart disease.
Homeodomain Nkx2-5-dependent Negative Feedback Loop Important In Heart Development And Congenital Heart Disease
Funder
National Health and Medical Research Council
Funding Amount
$1,330,245.00
Summary
Congenital heart disease (CHD) is the cause of most deaths in children in the first year of life. We have identified a genetic pathway important for both normal cardiac development and CHD that involves the cardiac transcription factor Nkx2-5. This pathway controls a transition in embryos between cardiac cell specification and expansion. We will now explore the biochemical and genetic mechanisms underlying this pathway to help us understand CHD and identify its causative genes.