A major feature of tumour progression and cardiac hypertrophy (enlarged heart) is accelerated cell growth and protein synthesis. Moreover, increased synthesis of ribosomes (the protein synthetic machinery) is associated with malignancy and hypertrophy suggesting that it may play a causal role in tumour formation and cardiac disease. In support of this, specific inhibitors of both ribosome biogenesis and function are extremely effective at inhibiting the growth of some tumours and vascular smooth ....A major feature of tumour progression and cardiac hypertrophy (enlarged heart) is accelerated cell growth and protein synthesis. Moreover, increased synthesis of ribosomes (the protein synthetic machinery) is associated with malignancy and hypertrophy suggesting that it may play a causal role in tumour formation and cardiac disease. In support of this, specific inhibitors of both ribosome biogenesis and function are extremely effective at inhibiting the growth of some tumours and vascular smooth muscle. This study will examine the mechanisms that regulate ribosome synthesis. Specifically it focuses on a transcription factor termed UBF whose activity we think is critical for the regulation of the synthesis of the ribosomal RNA, the catalytic backbone of the ribosomes. Understanding the molecular mechanism(s) controlling UBF function will lead to a better comprehension of how cells modulate synthesis of functional ribosomes and how this process is deregulated during disease states associated with deregulated protein synthesis and growth such as cardiac hypertrophy and cancer.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
A major feature ofcancer is accelerated cell growth and proliferation. One of the major rate-limiting processes that regulates cell growth is the 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. It wll also explore the hypothesis that dysregulation of ribosome biogeneis underlies and contributes to the aetiology of many human cancers.
Retrotransposon Regulation Of The Human Innate Immune Response
Funder
National Health and Medical Research Council
Funding Amount
$231,937.00
Summary
Complete sequencing of the human genome has revealed the positions of approximately 20,000 genes. In addition, nearly 50% of the human genome is comprised of repetitive sequences previously thought of as junk DNA. Numerous studies are now finding that this DNA actually has a variety of important functions, particularly in the control of gene activity. This project will examine the relationships between gene expression and nearby repetitive sequences during the innate immune response in humans.
Transcription Factors Which Regulate Signalling Through The Leptin-Melanocortin Pathway
Funder
National Health and Medical Research Council
Funding Amount
$586,704.00
Summary
Specific gene regulatory proteins define functions of various subsets of neurons in the hypothalamus. We will determine how interactions between three such proteins activate the leptin-melanocortin pathway, a hypothalamic signalling circuit that controls appetite. Defects in these proteins are found in obese patients who suffer from excessive eating disorders. The project will improve understanding of the genetic determinants of obesity and provide key points for development of new therapies.