Mechanisms By Which Chromatin Modulates Gene Expression.
Funder
National Health and Medical Research Council
Funding Amount
$267,750.00
Summary
Gene expression in a cell occurs in the nucleus where genes are stored. In the nucleus, DNA is not in a free form but is covered with an equivalent weight of protein to form a structure known as chromatin. Chromatin is a periodic structure made up of repeating, regularly spaced subunits, the subunit being the nucleosome. A nucleosome consists of a group of proteins (histones) wrapped around with DNA. A nucleosome is both capable of blocking and activating gene expression. Therefore one important ....Gene expression in a cell occurs in the nucleus where genes are stored. In the nucleus, DNA is not in a free form but is covered with an equivalent weight of protein to form a structure known as chromatin. Chromatin is a periodic structure made up of repeating, regularly spaced subunits, the subunit being the nucleosome. A nucleosome consists of a group of proteins (histones) wrapped around with DNA. A nucleosome is both capable of blocking and activating gene expression. Therefore one important function of chromatin is to tightly regulate gene expression which is essential to allow an organism to develop properly. When gene expression is not accurately controlled by chromatin developmental defects or cancer can result from the production of incorrect proteins. To control correct gene expression, highly specific mechanisms must operate in the cell to remove, or modify, nucleosomes at certain genes at a precise time during development. One mechanism that we believe to be important is changing the make-up of a nucleosome. This can be achieved in the cell by the replacement of histones with different specialized forms of these histones (variants). We believe that these histone variants can specifically generate chromosomal domains which could in some cases expose or in other cases hide certain genes and thereby turn them on or off. Employing a new approach, we will study one of these histone variants to discover the role it plays in determining the type of chromosomal domain made and the role of this domain has in turning genes on or off at precise times in early development during the formation of different specialized cell types. This new information may define targets for the prevention of incorrect gene expression during cancer progression or abnormal development.Read moreRead less
Trabecular Architecture During Growth - Does It Determine Metaphyseal Peak Bone Strength In Adulthood?
Funder
National Health and Medical Research Council
Funding Amount
$165,339.00
Summary
Skeletal fragility is common is elderly people but has its origin in childhood. Strong bone established during growth will provide more protection against occurrence of fragility fracture in old age. Identifying individuals during childhood who are at high risk of skeletal fragility, and early intervention is a strategic approach managing the burden of skeletal fragility on the ageing population.
Role Of The Growth Hormone Binding Protein As A Transcriptional Activator
Funder
National Health and Medical Research Council
Funding Amount
$387,226.00
Summary
Growth hormone is an important hormone therapeutic for treating dwarfism. Recently, many new therapeutic applications for growth hormone have been discovered, particularly in relation to its role as an anabolic agent. These include post surgery recovery, enhanced bone fracture healing, Crohns disease, dilated cardiomyopathy, infertility and of course, ageing. This proposal examines a novel way that GH could work, that is by sending the extracellular part of its receptor (GHBP) to the nucleus, wh ....Growth hormone is an important hormone therapeutic for treating dwarfism. Recently, many new therapeutic applications for growth hormone have been discovered, particularly in relation to its role as an anabolic agent. These include post surgery recovery, enhanced bone fracture healing, Crohns disease, dilated cardiomyopathy, infertility and of course, ageing. This proposal examines a novel way that GH could work, that is by sending the extracellular part of its receptor (GHBP) to the nucleus, where it can directly activate gene readout. This would have the effect of augmenting the normal action of GH to regulate gene readout. We have exciting preliminary data which makes us think this may be a new mechanism for hormone activation of genes. The level of GHBP in the nucleus is regulated, and if a defect in export of the GHBP occurred, this would lead to accumulation of nuclear GHBP and stimulate cell proliferation. This may be important in cancer cell proliferation, since we find nuclear GHBP in cancers.Read moreRead less
Regulation Of The Tumour Suppressors APC And BRCA1 By Nuclear Export
Funder
National Health and Medical Research Council
Funding Amount
$530,874.00
Summary
Cancer cells lack the ability to control their own growth, and thus continously divide in their local environment, leading to tumour formation. Tumour suppressor proteins, like APC and BRCA1, normally function as regulators to help cells respond to outside signals and to stop growing when necessary. The inactivation and altered cellular localisation of tumour suppressor proteins can contribute to cancer development. We have found that the APC and BRCA1 proteins, whose inactivation leads to devel ....Cancer cells lack the ability to control their own growth, and thus continously divide in their local environment, leading to tumour formation. Tumour suppressor proteins, like APC and BRCA1, normally function as regulators to help cells respond to outside signals and to stop growing when necessary. The inactivation and altered cellular localisation of tumour suppressor proteins can contribute to cancer development. We have found that the APC and BRCA1 proteins, whose inactivation leads to development of colon cancer and breast cancer, respectively, contain signals that dictate their movement within the cell. Our novel preliminary findings reveal that APC and BRCA1 are able to move in and out of the cell nucleus. We aim to define how this occurs, and examine how the regulation of their cellular location affects the normal function of these cancer-suppressing proteins. Finally, abnormalities in the nuclear passage of APC or BRCA1 might explain their altered cellular location in cancer cells.Read moreRead less
Maintenance Of Bone Strength In Aged Rats: The Vitamin D Requirement
Funder
National Health and Medical Research Council
Funding Amount
$543,301.00
Summary
Hip fracture remains the most devastating of the osteoporotic fractures particularly in women in whom the incidence increases to about 3% per annum by the ninth decade. This incidence is bound to increase as the population ages with increasing longevity. Supplementation of diets of elderly female nursing home residents with vitamin D and calcium has been shown to reduce the risk of hip fracture by 30% in two years. However we do not know how much vitamin D is necessary to maintain optimal bone s ....Hip fracture remains the most devastating of the osteoporotic fractures particularly in women in whom the incidence increases to about 3% per annum by the ninth decade. This incidence is bound to increase as the population ages with increasing longevity. Supplementation of diets of elderly female nursing home residents with vitamin D and calcium has been shown to reduce the risk of hip fracture by 30% in two years. However we do not know how much vitamin D is necessary to maintain optimal bone strength. This project will determine the level of vitamin D required to maintain optimal bone strength in aged rats using a simple blood test which could then be used to screen the elderly and identify those at risk of hip fracture from low vitamin D levels. The project will also investigate the effects of vitamin D on the bone cells that maintain optimal skeletal architecture. This information is essential for comparison with the current knowledge of other biochemical bone markets in blood and vitamin D status in the elderly, in order to develop nutritional recommendations to reduce the incidence of hip fracture.Read moreRead less
Hip fracture remains the most devastating of the osteoporotic fractures particularly in women, in whom the incidence increases to about 3% per annum by the ninth decade. This incidence is bound to increase as the population ages with increasing longevity. Supplementation of diets of elderly female nursing home residents with vitamin D and calcium has been shown to reduce the risk of hip fracture by 30% in two years. However we do not know how much vitamin D is necessary to maintain optimal bone ....Hip fracture remains the most devastating of the osteoporotic fractures particularly in women, in whom the incidence increases to about 3% per annum by the ninth decade. This incidence is bound to increase as the population ages with increasing longevity. Supplementation of diets of elderly female nursing home residents with vitamin D and calcium has been shown to reduce the risk of hip fracture by 30% in two years. However we do not know how much vitamin D is necessary to maintain optimal bone strength. This project will determine the level of vitamin Drequired to maintain optimal bone strength in adult and senescent rats using a simple blood test which could then be used to screen the elderly and identify those at risk a hip fracture from low vitamin D levels. The project will also investigate the effects of vitamin D on bone cells which is necessary to maintain optimal skeletal architecture. This information is essential for comparison with the current knowledge of other biochemical bone markers in blood and vitamin D status in the elderly, in order to develop nutritional recommendations to reduce the incidence of hip fracture.Read moreRead less
The Tumour Cell-specific Nuclear Targeting Properties Of Chicken Anaemia Virus VP-3: Potential For Anti-tumour Therapy
Funder
National Health and Medical Research Council
Funding Amount
$465,210.00
Summary
Current trends indicate that cancer will cause 40% of all deaths in Australia by 2012, meaning that new anti-cancer strategies are urgently required. Our proposal intends to examine the subcellular targeting abilities of the unique tumour-cell specific agent apoptin (VP3 - viral protein 3), a small protein encoded by the genome of the chicken anaemia virus. Using various strategies, we have identified part of the apoptin molecule that confers efficient localisation in the nucleus of tumour cells ....Current trends indicate that cancer will cause 40% of all deaths in Australia by 2012, meaning that new anti-cancer strategies are urgently required. Our proposal intends to examine the subcellular targeting abilities of the unique tumour-cell specific agent apoptin (VP3 - viral protein 3), a small protein encoded by the genome of the chicken anaemia virus. Using various strategies, we have identified part of the apoptin molecule that confers efficient localisation in the nucleus of tumour cells, but not non-tumour cells. Our experimental program intends to define this tumour cell-specific targeting signal in detail, and determine the molecular basis of the differential subcellular localisation of apoptin in tumour compared to normal cells. This should contribute fundamental new information regarding the differences between cancer and normal cells. Additionally, we intend to optimise the targeting signal and perform initial experiments to test its efficacy in targeting anti-tumour drugs to the nucleus of tumour cells. Our long-term aim is to use the apoptin tumour cell-specific nuclear targeting signal as part of modular constructs to combat cancer efficiently, and above all, with minimal damage to normal cells and tissues.Read moreRead less
Role Of IGF Binding Protein-3 (IGFBP-3) And IGFBP-5 As Modulators Of Nuclear Hormone Signalling
Funder
National Health and Medical Research Council
Funding Amount
$465,750.00
Summary
The insulin-like growth factors are small proteins involved in the growth of most tissues. Their actions are regulated by binding to larger proteins (known as IGFBPs) in the bloodstream and outside the cell. However, some IGFBPs are also found inside cells, where they seem to carry out other functions. We believe that two of these binding proteins, IGFBP-3 and IGFBP-5, change the way cells respond to vitamin A and vitamin D. These two vitamins are important in cell growth and in the way certain ....The insulin-like growth factors are small proteins involved in the growth of most tissues. Their actions are regulated by binding to larger proteins (known as IGFBPs) in the bloodstream and outside the cell. However, some IGFBPs are also found inside cells, where they seem to carry out other functions. We believe that two of these binding proteins, IGFBP-3 and IGFBP-5, change the way cells respond to vitamin A and vitamin D. These two vitamins are important in cell growth and in the way certain cells perform specialised functions. In test-tube experiments, IGFBP-3 and IGFBP-5 interact directly with the receptors that regulate the effects of these hormones. If the same thing happens inside the cell, IGFBP-3 and IGFBP-5 could change the way these receptors respond to signals from outside the cell. We will investigate what effect these IGFBPs have in living cells and in whole animals and how this may relate to human disease. If we are able to understand how IGFBP-3 and IGFBP-5 affect the way cells respond to vitamin A and D, then we may be able to develop new ways to treat certain human diseases.Read moreRead less