Structural And Biochemical Investigation Of The Bloom�s Complex, Defective In Bloom�s Syndrome
Funder
National Health and Medical Research Council
Funding Amount
$184,661.00
Summary
Bloom�s Syndrome is a rare inherited disorder that results in greater than 90% risk of developing cancer by the age of 25. The gene that causes Bloom�s Syndrome, called BLM, protects cells from cancer-causing mutations hence affected individuals develop the same types of cancers as the general population, only much faster. We will investigate the properties of the BLM gene product and understand how it protects us from cancer, and may influence some forms of cancer treatment.
Biochemical Reconstitution Of The Ubiquitin Ligase Pathway Defective In Fanconi Anaemia
Funder
National Health and Medical Research Council
Funding Amount
$562,742.00
Summary
Fanconi Anemia (FA) is characterised by loss of vital blood cells but also 700x risk of developing leukaemia and other cancers. FA is caused by an inherited defect in one of 15 different genes that provide a signal and repair mechanism protecting cells from cancer causing mutations. By reconstructing this signaling mechanism in the test tube we will determine how it contributes to cancer protection, and highlight potential strategies for treatment of FA and leukaemia in the general population.
FHA Domain-dependent Functions Of Cell Cycle Checkpoint Kinases
Funder
National Health and Medical Research Council
Funding Amount
$235,500.00
Summary
Human chromosomes as carriers of the genetic information are constantly subjected to DNA damage. This usually occurs spontaneously, simply as a result of oxidation of DNA residues as a byproduct of cellular energy consumption or as a result of errors during chromosome duplication in growing cells, and is compounded by chemical or physical agents, for example carcinogens, UV rays or X-rays. DNA damage can have severe consequences if not properly repaired, leading to genomic instability with loss ....Human chromosomes as carriers of the genetic information are constantly subjected to DNA damage. This usually occurs spontaneously, simply as a result of oxidation of DNA residues as a byproduct of cellular energy consumption or as a result of errors during chromosome duplication in growing cells, and is compounded by chemical or physical agents, for example carcinogens, UV rays or X-rays. DNA damage can have severe consequences if not properly repaired, leading to genomic instability with loss of vast tracts of DNA or inappropriate genome rearrangements, that may ultimately give rise to cancer. To prevent such dire consequences, all organisms from yeast to man contain molecular checkpoints that sense the presence of DNA damage and then activate a cellular response program that includes damage repair and prevention of cell division while damage persists. These molecular checkpoints are highly conserved throughout evolution which allows us to analyse the details involved in simple organisms such as yeast, to draw general conclusions on their function in more complex human cells. Along these lines, we are studying the function of two yeast proteins that are similar to the human Chk2 protein, a tumour suppressor that is mutated in a subset of families suffering from the Li-Fraumeni multi-cancer syndrome. We have identified new pathways by which these proteins contribute to the survival of cells after treatment with DNA damaging agents and will further charaterise these in the present proposal.Read moreRead less
DAMAGE TO SPECIFIC MITOCHONDRIAL MEMBRANE PROTEINS DURING OXIDATIVE STRESS AND THE AGEING PROCESS
Funder
National Health and Medical Research Council
Funding Amount
$195,982.00
Summary
During the ageing process and exposure to certain drugs or chemicals, oxygen radicals are produced within cells and tissues. If unchecked, these cause damage to a number of cell components, resulting in tissue death. One target for oxygen radicals are proteins in mitochondria, the powerhouses of the cell that are responsible for meeting cell energy needs. It is well known that the ability of mitochondria to maintain energy supplies decreases in old age. Over the past decade, research has shown t ....During the ageing process and exposure to certain drugs or chemicals, oxygen radicals are produced within cells and tissues. If unchecked, these cause damage to a number of cell components, resulting in tissue death. One target for oxygen radicals are proteins in mitochondria, the powerhouses of the cell that are responsible for meeting cell energy needs. It is well known that the ability of mitochondria to maintain energy supplies decreases in old age. Over the past decade, research has shown that this is partly due to mutation of genes in the DNA which is found in mitochondria. However it is also very likely that the loss of function in mitochondria during the ageing process is also due to the accumulation of protein damage. Recent work in insects has shown that specific proteins in mitochondria are extensively damaged during the ageing process and-or exposure to oxygen radicals. In higher organisms such as mice, however, exactly which mitochondrial proteins are targeted by oxygen radicals is unknown. This work will investigate the likelihood that proteins located in membranes of mitochondria are targets for damage by oxygen radicals and during the ageing process. Furthermore, since oxygen radicals readily attack polyunsaturated fatty acids in cell membranes, we are investigating the likelihood that toxic substances (unsaturated aldehydes) formed during membrane damage contribute to the damage to mitochondrial proteins during the ageing process.Read moreRead less
A Single-stranded DNA Binding Protein Implicated In The Cellular Response To DNA Damage.
Funder
National Health and Medical Research Council
Funding Amount
$503,816.00
Summary
Humans have evolved multiple mechanisms to ensure the integrity of their genetic information, which is carried by DNA. Each cell suffers more than 100 000 insults a day to its DNA; therefore an effective DNA damage response is crucial for the maintenance of genetic integrity and for survival. This research proposal aims to explore the molecular actions of hSSB2, a newly discovered player in the cell's arsenal for repairing harmful DNA damage.
Regulation And Function Of The Zinc-finger Protein ASCIZ In The DNA Damage Response
Funder
National Health and Medical Research Council
Funding Amount
$640,101.00
Summary
Each human cell is exposed to more than 10,000 spontaneous DNA damage events per day. Inaccurate repair of this is damage is believed to be one of the key events in the onset of cancer. We have discovered a protein called ASCIZ that contributes to the repair of DNA base damage, and also has a separate function in the onset of lung development. Here we want to study in detail the mechanism of how it functions in DNA repair and thereby keeps mutation rates low and prevents the onset of cancer.
DNA damage response pathways play important roles in preventing the onset of cancer and regulating the clinical response to chemotherapeutics, and some of the relevant proteins have additional functions during normal development. This fellowship will study new a human protein with key roles in the formation of the lung, and its roles in preventing devastating consequences of normal oxidative damage to DNA, as well as additional fundamental mechanisms involved in preventing genome mutations.
Heart attacks remain a major cause of morbidity and mortality. I am an interventional cardiologist who heads an expanding basic and translational science laboratory (Cardiac Oxidative Signalling) at the Kolling Institute and who plays a leading role in clinical cardiovascular research at Royal North Shore Hospital. My vision is to translate fundamental discoveries in our Laboratory to new therapies and methods of risk stratification to improve immediate and long term outcomes of patients sufferi ....Heart attacks remain a major cause of morbidity and mortality. I am an interventional cardiologist who heads an expanding basic and translational science laboratory (Cardiac Oxidative Signalling) at the Kolling Institute and who plays a leading role in clinical cardiovascular research at Royal North Shore Hospital. My vision is to translate fundamental discoveries in our Laboratory to new therapies and methods of risk stratification to improve immediate and long term outcomes of patients suffering heart attack.Read moreRead less