Contribution Of Disturbed Blood Flow And Cerebral Metabolism To White Matter Damage In The Perinatal Brain
Funder
National Health and Medical Research Council
Funding Amount
$369,375.00
Summary
It has been known for some time that the white matter regions of the developing brain are particularly vulnerable to damage. These regions are deep in the brain near the ventricles, and are rich in myelin sheaths wrapped around the nerve fibres running from cell-rich areas in the outer layers of the brain to other regions, and down into the spinal cord. Damage to white matter usually leads to behavioural, learning and motor problems in the newborn infant - in its severest form, seen as cerebral ....It has been known for some time that the white matter regions of the developing brain are particularly vulnerable to damage. These regions are deep in the brain near the ventricles, and are rich in myelin sheaths wrapped around the nerve fibres running from cell-rich areas in the outer layers of the brain to other regions, and down into the spinal cord. Damage to white matter usually leads to behavioural, learning and motor problems in the newborn infant - in its severest form, seen as cerebral palsy. Such outcomes are often associated with the presence of asphyxia and infection during pregnancy, leading to the belief that the damage first arises while the baby is still in utero. In this application we suggest that asphyxia and-or infection during pregnancy cause prolonged disturbances in the regulation of blood flow and integrity of the blood-brain barrier in the developing brain, together with changes in metabolism that result in accumulation of prostaglandins and the toxic hydroxyl radical, leading irreversibly to cell death. If this series of events proves to be true, we have suggested and will test several protocols for protecting the fetal brain, which should be readily translatable to clinical practice.Read moreRead less
The Role Of Nuclear Architecture In The DNA Damage Response
Funder
National Health and Medical Research Council
Funding Amount
$561,966.00
Summary
The goal of the proposed research is to understand how dynamic changes to the chromatin genome packaging network, interact with the DNA damage response and gene expression machinery, to repair damaged DNA and the impact this has on cancer biology. To do so we are combining cutting edge molecular biology techniques with innovative novel microscopy methods developed by our research team, that far exceed the spatiotemporal resolution currently used to study chromatin biology.
Galectin-3 And Phagocyte Function In Severe Asthma
Funder
National Health and Medical Research Council
Funding Amount
$698,084.00
Summary
Asthma, a major chronic inflammatory disease affects more than 2 million Australians. Neutrophilic severe asthma is not responsive to current therapies. We have recently made a significant advance in understanding neutrophilic asthma, reporting low levels of a protein called galectin-3 (gal-3). In this project we will explore the role of gal-3 its effect on the resolution of inflammation. This study will result significantly advance the knowledge of the mechanisms of neutrophilic severe asthma.
How Replication Stress Activates The Mitotic Telomere DNA Damage Response To Kill Cancer Cells
Funder
National Health and Medical Research Council
Funding Amount
$486,467.00
Summary
We discovered a novel mechanism linking stress during DNA replication to difficulties with the cell division process, and identified how this turns on DNA damage response signals from the chromosome ends (i.e. “telomeres”). We have further identified that we can exploit this mechanism to kill cancer cells. In this project we will explore this newly discovered mechanism and identify how it can be targeted for therapeutic purposes.
Long-term Nerve Damage In Cancer Survivors: Identification Of Risk Factors And Optimal Assessment Strategies
Funder
National Health and Medical Research Council
Funding Amount
$850,172.00
Summary
Nerve damage following chemotherapy treatment leads to early treatment cessation and long-lasting disability, developing with commonly used chemotherapies. There is a critical need to understand the mechanisms, optimize clinical assessment and develop interventions to prevent nerve damage. This project is designed to detect the impact of long-term nerve damage in cancer survivors and develop a risk profile based on clinical, neurophysiological and genetic factors.
Ubiquitin And SUMO DNA Damage Response Signalling At Deprotected Telomeres During The Cell Cycle
Funder
National Health and Medical Research Council
Funding Amount
$302,627.00
Summary
Following genome damage cells stop the cell division process and initiate DNA repair. We discovered that at specific times during cell division his does not happen if the damage signals originate from the chromosome ends (i.e. “telomeres”). We anticipate this is necessary to prevent genomic instability in healthy cells and may be driving genomic instability in cancer cells. Experiments described here will elucidate the molecular mechanisms and biological significance of our observation.
Neurosteroid Mediated Protection After Birth: Approaches For Maximising Protective Steroid Levels In The Neonatal Brain
Funder
National Health and Medical Research Council
Funding Amount
$450,703.00
Summary
Complications during pregnancy, birth asphyxia or premature birth can lead to neurological impairment in the newborn. Despite excellent neonatal care many of these babies go on to have serious handicaps. Neurosteroids are a group of steroids that regulate brain activity. These steroids protect brain cells from damage caused by an inadequate supply of oxygen by suppressing toxicity caused by excessive activity. We have shown that the levels of these protective steroids are remarkably high in the ....Complications during pregnancy, birth asphyxia or premature birth can lead to neurological impairment in the newborn. Despite excellent neonatal care many of these babies go on to have serious handicaps. Neurosteroids are a group of steroids that regulate brain activity. These steroids protect brain cells from damage caused by an inadequate supply of oxygen by suppressing toxicity caused by excessive activity. We have shown that the levels of these protective steroids are remarkably high in the fetal brain and levels rise further in response to fetal stress. The placenta contributes steroid precursors that help maintain these high neurosteroid levels. This placenta-fetal brain interaction comprises an internal mechanism that protects the fetal brain from adverse events during pregnancy. At birth, however, there is a dramatic decline in neurosteroid concentrations in the brain after the loss of the placental precursor supply. The fall in concentrations is even greater in animals that are born growth restricted. This suggests that newborns, particularly those from compromised pregnancies, are at increased risk of brain damage due to low neurosteroid levels. We believe that certain commonly used steroid therapies may also lower steroid levels in the brain and result in increased vulnerability to brain damage during birth or in the early neonatal period. Alternatively, we propose that replacement of neurosteroid precursors in the newborn may raise brain neurosteroid levels and protect against brain damage. In the proposed studies we will evaluate treatments that can raise the concentration of steroids and determine the best strategy for reducing brain injury following complications during pregnancy, at birth and during the early newborn period. This work will determine the best therapeutic approaches for maximising neurosteroid-induced brain protection and for reducing the risk of brain damage.Read moreRead less
Improved Formulations Of Anti-cancer Agents 5-Fluorouracil And Oxaliplatin Using Excipient Technology
Funder
National Health and Medical Research Council
Funding Amount
$202,973.00
Summary
Chemotherapy plays a key role in cancer treatment, however, problems persist with severe adverse toxic effects. Combinations of anti-cancer agents give better results, but these agents still have major negative effects, for example, on veins and peripheral nerves and they must be given separately. We have developed a novel, all-in-one formulation of Oxaliplatin with 5-Fluorouracil and Leucovorin, with the potential for fewer toxic effects and improved patient care.
A Novel Macrophage Lineage In Inflammation And Cancer
Funder
National Health and Medical Research Council
Funding Amount
$772,857.00
Summary
Macrophages are an important haematopoietic cell type that has been implicated in inflammatory and cancerous diseases. In our preliminary work we have discovered a new macrophage subset, termed the perivascular macrophage, in breast cancer. The aim of this proposal is to investigate the origin of these cells, and the role they play in breast cancer. This will tell us how we might be able to manipulate the functions of these cells in order to curtail breast cancer progression.
Gene Expression Biomarkers Predict Severe Asthma Inflammatory Phenotype, Activation Mechanisms And Treatment Response
Funder
National Health and Medical Research Council
Funding Amount
$465,627.00
Summary
Asthma is now recognised to be made up of several disease variants or phenotypes, which are likely to have different underlying causes and mechanisms. We lack understanding of how to identify phenotypes of asthma and how they work, and this is delaying research that will lead to improvements in treatments and patient care. This is particularly important in people with severe disease. This grant will establish a gene test to identify asthma phenotype, and further understand mechanisms and treatme ....Asthma is now recognised to be made up of several disease variants or phenotypes, which are likely to have different underlying causes and mechanisms. We lack understanding of how to identify phenotypes of asthma and how they work, and this is delaying research that will lead to improvements in treatments and patient care. This is particularly important in people with severe disease. This grant will establish a gene test to identify asthma phenotype, and further understand mechanisms and treatment responses.Read moreRead less