Regulation Of Ribosomal Gene Transcription By C-MYC During Differentiation And Lymphomagenesis.
Funder
National Health and Medical Research Council
Funding Amount
$287,261.00
Summary
A fundamental question in medical biology revolves around how cells respond to the demands to grow and produce proteins, particularly in the setting of the rapid growth of cancer cells. One of the important facets of cellular growth is the production of new proteins needed for all areas of cell life. It is well known that cellular growth involves the production of proteins and this in turn requires the transcription or duplication of ribosomal RNAs (rRNAs). The control of rRNA synthesis, however ....A fundamental question in medical biology revolves around how cells respond to the demands to grow and produce proteins, particularly in the setting of the rapid growth of cancer cells. One of the important facets of cellular growth is the production of new proteins needed for all areas of cell life. It is well known that cellular growth involves the production of proteins and this in turn requires the transcription or duplication of ribosomal RNAs (rRNAs). The control of rRNA synthesis, however, is not well understood. We have identified a novel process to link a cancer causing gene c-MYC to the control of protein production in cells through regulation of rRNA synthesis. Our experiments will examine the hypothesis that c-MYC directly affects the production of rRNA . Finally we will test the link between the ability of c-MYC to cause malignant growth of cells and its role in increasing synthesis of rRNA. These findings may lay the basis for new treatments for disorders of regulated cell growth such as cancer.Read moreRead less
Enrichment, Differentiation And Functional Analysis Of Growth Hormone Progenitor Cells From The Adult Mouse Pituitary
Funder
National Health and Medical Research Council
Funding Amount
$469,500.00
Summary
Many important bodily functions including growth, metabolism, onset of puberty, fertility, lactation and the ability to cope with stress are controlled by hormones secreted by the pituitary gland. Consequently, insufficient hormone production by the pituitary gland (hypopituitarism) results in life-threatening conditions which are a significant clinical problem. Growth Hormone (GH) deficiency is the most common form of pituitary hormone deficiency, affecting 1:3,500 individuals. Currently, GH de ....Many important bodily functions including growth, metabolism, onset of puberty, fertility, lactation and the ability to cope with stress are controlled by hormones secreted by the pituitary gland. Consequently, insufficient hormone production by the pituitary gland (hypopituitarism) results in life-threatening conditions which are a significant clinical problem. Growth Hormone (GH) deficiency is the most common form of pituitary hormone deficiency, affecting 1:3,500 individuals. Currently, GH deficiency is treated by daily injections of growth hormone at a cost of $30,000 to $50,000 per patient per annum. However, even with daily injections and despite the cost, it is difficult to mimic the naturally fluctuating hormone levels in the body, resulting in incomplete growth rescue. Long term injections also have severe side effects that can lead to cardiovascular problems, abnormal bone density, diabetes and cancers of various types. To overcome the disadvantages of hormone therapy we are investigating a new cell replacement therapy to treat GH deficiency. This approach requires knowledge about the mechanism by which GH-secreting cells are generated and maintained in the adult pituitary. For the first time, we have isolated a type of progenitor (unspecialised) cell from adult mouse pituitary that is capable of dividing and generating GH-secreting cells. Our current research aims to further purify these cells and to show that they are capable of secreting GH in response to biologically relevant signals. In addition, we will test whether these cells can grow and develop into functional cells when introduced into mice. In particular, we will test whether the progenitor cells can rescue dwarfism using a mouse model of GH deficiency. This pioneering study will provide the first insight into the possibility of cell therapy for the pituitary, and may ultimately lead to the development of better therapies for patients with GH deficiency.Read moreRead less
UNDERSTANDING THE MOLECULAR MECHANISMS CONTROLLING NUCLEOLAR SURVEILLANCE IN DISEASE
Funder
National Health and Medical Research Council
Funding Amount
$855,972.00
Summary
Alterations in the ability of cells to make ribosomes, the cellular factories that make protein, contribute to a range of diseases including cancer and a class of inherited disorders called ribosomopathies that are rare but largely untreatable. These changes cause disease by controlling the “nucleolar surveillance pathway” that causes cells to either stop dividing or die. Here we propose to identify new genes that regulate this pathway to identify new targets for treating these diseases.
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
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.
Wbp2, A New Regulator Of The Hippo Tumor Suppressor Pathway
Funder
National Health and Medical Research Council
Funding Amount
$585,860.00
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 a newly-identified Hippo pathway protein, Wbp2, functions to control growth. These studies will be performed in flies and confirmed in mammalian cells. Ultimately, 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.
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 different transcription factors in the Hippo pathway operate to control tissue growth. 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.
Mechanisms For Regulation Of Myc Transcription And Cell Growth
Funder
National Health and Medical Research Council
Funding Amount
$645,347.00
Summary
We aim to use the animal model system, the vinegar fly, to investigate mechanism for cancer initiation. The fly has been studied for over 90 years and has proved an excellent genetic model for understanding the complex processes leading to abnormal cell growth, which is associated with the early stages of human cancer. The high level of conservation between fly genes and human cancer genes means these studies will provide novel insights into the genetic mechanisms underlying tumour formation.
The Hippo Pathway, Neural Stem Cells And Brain Growth
Funder
National Health and Medical Research Council
Funding Amount
$363,137.00
Summary
During organism development, the brain grows to the right size without overgrowing. Neural stem cells are key regulators of brain size. We will define how the Hippo pathway crosstalks with nutrition-induced signals to control proliferation of neural stem cells and brain size. As well as producing important insights into normal growth, we will increase our understanding of brain diseases associated with aberrant brain growth, such as cancer.