The Nuclear Growth Hormone Receptor- Its Actions And Mechanism Of Nuclear Translocation
Funder
National Health and Medical Research Council
Funding Amount
$531,696.00
Summary
We and others have found that cell surface receptors for growth factors such as EGF, FGF and growth hormone can be found in the nucleus of proliferating cells. We have shown that many cancers have elevated nuclear GH receptor including leukemia, breast and colon cancer. If we artificially target the GH receptor to the nucleus, the resulting cells are tumorigenic when injected into immunocompromised mice, rapidly form ing metastasising tumours. To create more effective inhibitors of this tumourog ....We and others have found that cell surface receptors for growth factors such as EGF, FGF and growth hormone can be found in the nucleus of proliferating cells. We have shown that many cancers have elevated nuclear GH receptor including leukemia, breast and colon cancer. If we artificially target the GH receptor to the nucleus, the resulting cells are tumorigenic when injected into immunocompromised mice, rapidly form ing metastasising tumours. To create more effective inhibitors of this tumourogenesis, and to define the physiological roles of nuclear GH receptor, we will define the transport process which carries the receptor to the nucleus and block it. We will also seek to define how the receptor in the nucleus interacts directly with DNA to inhibit programmed cell death. To carry out these projects we will use sophisticated proteomics -mass spectrometry to identify the proteins interacting with the receptor in the transport and gene activation processes. The role of candidates will be tested by preventing their expression or by direct inhibition of their action using drugs or dominant negative versions. These approaches will provide leads to new anti-cancer therapeutics, and therapies for blocking diabetic blindness and kidney failure.Read moreRead less
Molecular And Cellular Mechanisms Of Axon Guidance In The Vertebrate Nervous System
Funder
National Health and Medical Research Council
Funding Amount
$330,735.00
Summary
There are, at least, two major obstacles that have to be overcome in the design of therapies to assist the repair of injured brain tissue. First, the nerve cells that are damaged have to be encouraged to regrow - typically this regrowth is inhibited in the brain; and second, this regrowth has to be directed so that the correct connections are re-established. This project will begin to unravel some of the mechanisms that nerve cells use to wire up together during development. This information can ....There are, at least, two major obstacles that have to be overcome in the design of therapies to assist the repair of injured brain tissue. First, the nerve cells that are damaged have to be encouraged to regrow - typically this regrowth is inhibited in the brain; and second, this regrowth has to be directed so that the correct connections are re-established. This project will begin to unravel some of the mechanisms that nerve cells use to wire up together during development. This information can be used to assist in trying to modulate and facilitate directed regrowth following injury.Read moreRead less
Defining The Epigenetic Origins Of Maternally Inherited Disease.
Funder
National Health and Medical Research Council
Funding Amount
$731,162.00
Summary
Epigenetic (non genetic) changes to the DNA in sperm and eggs can alter outcomes in children. Despite the potential for drugs and diet to mediate some of these inherited effects, the processes involved are very poorly understood. By determining the mechanisms that regulate epigenetic inheritance, this project will improve our understanding of how epigenetic mechanisms acting in the parent, can mediate inherited disease and life-long health outcomes in our children.
Novel Methods For Promoting Organ Development And Growth
Funder
National Health and Medical Research Council
Funding Amount
$390,203.00
Summary
A revolutionary new therapy for treatment of growth restricted fetuses and premature babies is being developed through the administration of Colony Stimulating Factor (CSF-1). We have evidence that CSF-1 therapy can promote kidneys and lungs to continue development and maturation after birth. This exciting new finding allows for the application of CSF-1 therapy for both the treatment of premature babies and unborn babies with kidney defects.
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
Globally, zebrafish are making a very significant impact on biomedical research. Zebrafish have a number of attributes that make them ideal models for the study of development and disease, including: - adults are relatively small, so housing is cheap - eggs are transparent, so early developmental processes can be visualized easily - development is rapid - organs are made in 1-7 days - zebrafish are vertebrates and thus have a gene complement very similar to humans - large numbers of eggs are pro ....Globally, zebrafish are making a very significant impact on biomedical research. Zebrafish have a number of attributes that make them ideal models for the study of development and disease, including: - adults are relatively small, so housing is cheap - eggs are transparent, so early developmental processes can be visualized easily - development is rapid - organs are made in 1-7 days - zebrafish are vertebrates and thus have a gene complement very similar to humans - large numbers of eggs are produced each week from a single mother, aiding experimentation - ENU mutagenesis screens have generated thousands of useful mutants, including an increasing number that accurately model human genetic diseases - high-resolution imaging of RNA and protein expression in whole embryos is easy - drugs and chemicals can be easily tested for activities in zebrafish by adding them to the water Becuase of these attributes, zebrafish are becoming the model organism of choice for the study to human development and disease - indeed, the zebrafish field is growing at three times the rate of the mouse field. The international biomedical community has invested very heavily in infrastructure to aid the zebrafish community in realising the potential of this model. In Australia we have very strong basic research teams whom have embraced zebrafish mdoels. However, we lag behind other parts of the world in that, as yet, we have not had much specific funding allocated to animal model infrastructure. This Enabling Grant will build unique infrastructure by bringing together the zebrafish community with two areas in which Australia is very strong - genomics and biodiversity. This will result in a greatly enhanced ability to determine how genes work, and a pipeline for screening Australia's rich source of natural products and chemical libraries for activites against common human diseases such as cancer, dementia, and muscle diseases using zebrafish models.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.
Characterisation Of Neuregulin-2 Function In The Nervous System.
Funder
National Health and Medical Research Council
Funding Amount
$183,250.00
Summary
The Neuregulins (NRG's) are a family of four structurally related growth factors expressed in the developing and adult brain. NRG-1 is essential for life and has been implicated in the development and maintenance of both neurons and glial cells, as well as being essential for normal heart formation. NRG-2 was identified by us and others as being closely related to NRG-1 and, like NRG-1, it is also expressed predominantly in neuronal populations of the brain. One striking feature of NRG-2 express ....The Neuregulins (NRG's) are a family of four structurally related growth factors expressed in the developing and adult brain. NRG-1 is essential for life and has been implicated in the development and maintenance of both neurons and glial cells, as well as being essential for normal heart formation. NRG-2 was identified by us and others as being closely related to NRG-1 and, like NRG-1, it is also expressed predominantly in neuronal populations of the brain. One striking feature of NRG-2 expression in the adult brain is its localisation to regions associated with neurogenesis (renewal of neurons from stem cell precursors). Outside the nervous system Neuregulin-2 can stimulate the proliferation and differentiation of epithelial cells. However, little is known about the activity of Neuregulin-2 in the brain. This grant proposal aims to study the biological functions of Neuregulin-2 in the developing and adult central nervous system. The experimental design is based on characterisation of mice that do not contain the Neuregulin-2 gene. We will also look specifically at the action of Neuregulin-2 on discrete populations of neuronal cells, grown in tissue culture. We expect that these studies will provide valuable insight into the role of NRG-2 in the brain and that they will be the basis for defining the mechanisms by which NRG-2 activity differs to that of the NRG family members. By studying factors that are involved in the development of the nervous system it is hoped that valuable insights will be made regarding repair and regeneration in the adult brain.Read moreRead less
Molecular And Activity Dependent Mechanisms Regulating The Targeting Of Corpus Callosum Axons In The Contralateral Hemisphere.
Funder
National Health and Medical Research Council
Funding Amount
$413,266.00
Summary
The brain is made up of circuits of neurons that process specific information. For example, the somatosensory cortex receives and sends connections to other somatosensory areas, including the contralateral cortex, but how these systems are wired up is not known. We will investigate whether information about the size and position of the cortical areas and activity-matching of the somatosensory information received by each hemisphere are used to guide callosal axons to their targets.