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
GTPase Regulation Of The Hippo Organ Size-control Pathway
Funder
National Health and Medical Research Council
Funding Amount
$570,334.00
Summary
The Hippo pathway is a key regulator of tissue growth. It was first discovered in vinegar flies and plays a similar role in mammals. We aim to define the mechanism by which two proteins, Pix and Git, control tissue growth by regulating the Hippo pathway. These studies will be performed in flies. Our studies will shed light on how tissue growth is controlled, and have the potential to inform the way that we treat human cancers and tissue growth disorders.
Examination Of The Mechanism By Which The Salvador/warts/hippo Complex Restricts Cell Growth And Number
Funder
National Health and Medical Research Council
Funding Amount
$283,767.00
Summary
Cancer is a disease that results from the generation of surplus cells. These extra unwanted cells are produced as a result of excess cell proliferation and impaired programmed cell death. These important processes can be deregulated in cancers as a result of mutations in many different genes. Many genetic lesions have been reported in different types of cancers but many of the genes that are mutated in these diseases have yet to be identified. To isolate new genes involved in cancer we created r ....Cancer is a disease that results from the generation of surplus cells. These extra unwanted cells are produced as a result of excess cell proliferation and impaired programmed cell death. These important processes can be deregulated in cancers as a result of mutations in many different genes. Many genetic lesions have been reported in different types of cancers but many of the genes that are mutated in these diseases have yet to be identified. To isolate new genes involved in cancer we created random mutations in the vinegar fly, Drosophila, and tested their ability to cause solid cancers. Drosophila is an excellent model organism for this study because many of the pathways that are often perturbed in cancer are conserved between humans and flies. Using this approach we identified several known and novel genes that cause cancerous growths. By studying the human counterparts of these novel genes we identified a potential role for some of these genes in the generation of human cancer. Three of these genes, hippo, salvador and warts, appear to act in concert to restrict cell number. In this study we aim to understand the mechanism by which these genes restrict cell number. To do this we will analyze how the activity of this pathway is controlled and in what tissues it functions. We also plan to discover other key components of this pathway that function downstream of hippo, salvador and warts. To perform these experiments we will use a variety in vitro biochemical techniques as well as experiments in tissue culture cells. We will then verify the results of these experiments in the context of a whole animal. By performing these experiments we hope to gain greater insight into the genesis of cancer.Read moreRead less
Tao Kinase, A New Member Of The Hippo Tumour Suppressor Pathway
Funder
National Health and Medical Research Council
Funding Amount
$605,190.00
Summary
The Hippo pathway is a key regulator of tissue growth. It was first discovered in vinegar flies and plays a similar role in mammals. We aim to define the mechanism by which the Tao kinase controls tissue growth by regulating the Hippo pathway. These studies will be performed in flies and mammalian cell culture. Our studies will shed light on how tissue growth is controlled, and have the potential to inform the way that we treat human cancers and tissue growth disorders.
Deregulation Of Ribosome Signalling, Synthesis And Function During Malignant Transformation.
Funder
National Health and Medical Research Council
Funding Amount
$522,773.00
Summary
A major feature of tumour progression is accelerated cell growth and protein synthesis. Moreover, increased synthesis of ribosomes (the protein synthetic machinery) is associated with malignancy suggesting that it may play a causal role in cancer formation. In support of this, specific inhibitors of both ribosome biogenesis and function are extremely effective in inhibiting the growth of some tumours. This study will examine the mechanisms of deregulation of ribosome biogenesis and function duri ....A major feature of tumour progression is accelerated cell growth and protein synthesis. Moreover, increased synthesis of ribosomes (the protein synthetic machinery) is associated with malignancy suggesting that it may play a causal role in cancer formation. In support of this, specific inhibitors of both ribosome biogenesis and function are extremely effective in inhibiting the growth of some tumours. This study will examine the mechanisms of deregulation of ribosome biogenesis and function during cancer formation and assess for the first time whether aberrant regulation of ribosome biogenesis and function directly contributes to the initiation and-or progression of cancer.Read moreRead less
Regulation Of Growth Hormone Profile By Metabolic Balance: Neuronal, Neuroendocrinal And Molecular Mechanism
Funder
National Health and Medical Research Council
Funding Amount
$413,257.00
Summary
Obesity is associated with a reduction in growth hormone secretion. As growth hormone maintains muscle mass at the expense of fat this may further promote the obese condition. This project will determine the physiological role of ghrelin, a hormone that signals hunger, in maintaining growth hormone secretion under normal, fasting and obese conditions. Clarification of the role of ghrelin in regulating growth hormone secretion may aid in the development of pharmacological agents to assist and mai ....Obesity is associated with a reduction in growth hormone secretion. As growth hormone maintains muscle mass at the expense of fat this may further promote the obese condition. This project will determine the physiological role of ghrelin, a hormone that signals hunger, in maintaining growth hormone secretion under normal, fasting and obese conditions. Clarification of the role of ghrelin in regulating growth hormone secretion may aid in the development of pharmacological agents to assist and maintain weight loss.Read moreRead less
Stem cell to differentiation occurs in a bi-directional fashion. Dedifferentiation which allows specialized cells to become stem cells has been found to be important in both cancer and regeneration. In this proposal, we will investigate the metabolic reprogramming of neuronal dedifferentiation. The findings from this study will better inform us on how to specifically target tumours that arise from dedifferentiation.
Mammalian cells have developed a complex signalling network responsible for monitoring and responding to changes in the levels of growth factors and the availability of nutrients, energy and oxygen in their environment. Deregulation of this network often results in uncontrolled cell growth and diseases including cardiac hypertrophy and cancer. This proposal aims to understand how this network controls cell growth and identify potential targets for diseases driven by uncontrolled growth.