The Effect Of Anti-fibrinolytic Drugs On Blood-brain Barrier Integrity And The Immune Response In Traumatic Brain Injury
Funder
National Health and Medical Research Council
Funding Amount
$870,476.00
Summary
This project aims to determine how a well known anti-fibrinolytic drug can improve the immune response and reduced blood brain barrier disruption following traumatic brain injury. We will also be testing additional drugs we have developed as well as a novel drug delivery system that better targets drugs to the damaged brain.
Treatment Of Cerebral Palsy - An Experimental Approach
Funder
National Health and Medical Research Council
Funding Amount
$589,544.00
Summary
Cerebral palsy is characterised by disordered movement evident early in life leading to lifelong disability. The motor disorder arises from an abnormality within the white-matter of the brain that is non-progressive and is identifiable soon after birth. In humans and experimental models of fetal infection there is an increase in markers of inflammation. We will use induce ovine fetal infection and white matter injury to examine if anti-inflammatory treatments can prevent fetal brain damage.
Measurement Of Residual Nervous System Function After Spinal Cord Injury
Funder
National Health and Medical Research Council
Funding Amount
$779,159.00
Summary
Multiple serial physiological recording techniques will be used to assess sensory and motor function for 12 months after spinal cord injury. This detailed information will provide, for the first time, an insight into the changes, both beneficial and deleterious, in the sensory and motor systems over time. Such information may enable changes in the management of people with spinal cord injury to prevent deleterious effects on the nervous system and enhance function.
Alternate Signalling Pathways Regulating The Human Arachidonate Epoxygenase CYP2J2 In Response To Stress Stimuli
Funder
National Health and Medical Research Council
Funding Amount
$369,000.00
Summary
Hypoxia, or oxygen deprivation, is caused by the decreased supply of blood to cells and is a component of ischaemic injury to the cardiovascular system (e.g. stroke, atherosclerosis) and numerous other organs (e.g. cancer and chemical mediated injury). It is now known that an important group of proteins that switch on specialised target genes in response to hypoxia is Activator-Protein-1 (AP-1). We have found that cytochrome P450 2J2 (CYP2J2), which is an enzyme that forms beneficial fatty acid ....Hypoxia, or oxygen deprivation, is caused by the decreased supply of blood to cells and is a component of ischaemic injury to the cardiovascular system (e.g. stroke, atherosclerosis) and numerous other organs (e.g. cancer and chemical mediated injury). It is now known that an important group of proteins that switch on specialised target genes in response to hypoxia is Activator-Protein-1 (AP-1). We have found that cytochrome P450 2J2 (CYP2J2), which is an enzyme that forms beneficial fatty acid products inside cells, is decreased in hypoxia and that this is due to increased activity of AP-1. We know that similar stressful stimuli can also result in a loss of CYP2J2. Again, AP-1 is involved but we have further evidence for the role of another pathway. This project will explore how these pathways operate individually and together to decrease CYP2J2. Studying the regulation of human genes is difficult because we can not readily monitor their levels in cells in either healthy or sick individuals. So we will make transgenic mouse models to study human CYP2J2 regulation, which will provide information on the human situation. In this project we will identify which factors switch off the CYP2J2 transgene and will analyse the signalling pathways within cells that control this response. The importance of these studies is that they will help us to design pharmacological strategies to prevent the loss of CYP2J2 in cells that are stressed. Such agents may be effective in the treatment of ischaemic injury seen in stroke and atherosclerosis. If we can maintain CYP2J2 levels we may be able to maintain the beneficial fatty acid levels in cells and have a novel therapeutic approach for keeping cells alive.Read moreRead less
IMMUNE-MEDIATED INFLAMMATION IN DORSAL ROOT GANGLIA AFTER PERIPHERAL NERVE INJURY AND IN SENSORY NEUROPATHIES
Funder
National Health and Medical Research Council
Funding Amount
$378,300.00
Summary
Damage to the nervous system can occur because of accidental or iatrogenic trauma, toxins, infection, metabolic disorders, and even normal ageing. The consequences can outweigh the direct effects of the injury. Almost all injury to the nervous system results in loss of nerve cells and consequently modified sensation and movement. Nerve damage may also be followed by sensory disturbances, ranging from tingling, numbness and abnormal temperature sensations to spontaneous pain, allodynia (painful s ....Damage to the nervous system can occur because of accidental or iatrogenic trauma, toxins, infection, metabolic disorders, and even normal ageing. The consequences can outweigh the direct effects of the injury. Almost all injury to the nervous system results in loss of nerve cells and consequently modified sensation and movement. Nerve damage may also be followed by sensory disturbances, ranging from tingling, numbness and abnormal temperature sensations to spontaneous pain, allodynia (painful sensations from light touch) or hyperalgesia (increased sensitivity to a damaging stimulus). Some of these symptoms are encountered in older people as they lose sensory neurones. The problems are chronic and most are intractable to drugs. This project will clarify how immune-mediated inflammation of dorsal root (sensory) ganglia (DRGs) contributes to these sequelae. Even the simplest form of neural damage following peripheral nerve injury can produce changes in regions of the nervous system far from the parts directly involved in the injury. Our recent work has described for the first time the involvement of the immune system in triggering changes in DRGs following transection of a distant peripheral nerve in rats. T-cell activation leads to invasion of macrophages and production of proinflammatory cytokines. These substances can activate sensory neurones and may be responsible for progressive neuronal death. Thus we have established a simple system in which we can evaluate the influx of T-cells and macrophages of different kinds into DRGs after injury and other insults. We intend to use this to define the sequence of cellular events involved in recruitment of immune cells and compare it with other experimental interventions known to produce a neuroimmune response in this system. This will identify whether the DRG is a special site for neuroimmune interactions and so should be a target for therapy.Read moreRead less
The Host Response To Highly Pathogenic Influenza Virus
Funder
National Health and Medical Research Council
Funding Amount
$237,981.00
Summary
Highly pathogenic influenza infections are a global health concern and cause global panic. There is no effective therapy available; for example and the death rate for H5N1 infection is ~60%. Here we propose to further understand host lung response to highly pathogenic influenza with a view to develop new therapies for this urgent issue.
Roles Of Injury-induced Inflammatory Response In Regulating Bony Repair At Injured Growth Plate Cartilage
Funder
National Health and Medical Research Council
Funding Amount
$366,301.00
Summary
Children's growth plate cartilage is responsible for bone lengthening. Due to popularity of sports and play, trauma-induced growth plate damage and subsequently bone growth defects are common in children, with up to 30% of growth plate injury cases resulting in growth abnormality, for which the present surgical correction is highly invasive and not fully effective. Although we know that the growth plate injury-induced bone growth defects result from bony repair of the injured growth cartilage, w ....Children's growth plate cartilage is responsible for bone lengthening. Due to popularity of sports and play, trauma-induced growth plate damage and subsequently bone growth defects are common in children, with up to 30% of growth plate injury cases resulting in growth abnormality, for which the present surgical correction is highly invasive and not fully effective. Although we know that the growth plate injury-induced bone growth defects result from bony repair of the injured growth cartilage, we largely don't understand why and how this bony repair occurs. Understanding mechanisms for this faulty bony repair of injured growth plate will be critical prior to effective biological treatments can be developed. Recently, using an injury model in young rats, we found that bony tissue formation at injured growth plate is preceded sequentially by inflammatory, fibrogenic, chondrogenic and osteogenic responses. The inflammatory response is an initial event and our recent studies suggest that inflammatory response recruits inflammatory cells and produces important molecules that could significantly influence subsequent fibrogenic, chondrogenic and osteogenic events leading to the bony repair of the injured growth plate cartilage. The current proposal further addresses roles of the inflammatory response and the molecular pathways of this response in regulating downstream bony repair events. This project will generate novel understanding on the faulty bony repair of injured growth plate, and will provide valuable information for developing cost-effective and simple therapeutic intervention that aims to prevent bony repair and to enhance cartilage regeneration of the injured growth plate in children.Read moreRead less
Immunotoxic Effects Of Engineered Nanomaterials Used In The Australian Workplace
Funder
National Health and Medical Research Council
Funding Amount
$586,816.00
Summary
Certain engineered nanomaterials are more toxic than their bulk material forms. We urgently need the ability to re-engineer these nanomaterials to reduce their toxicity and potential health risks, but lack the necessary knowledge. This project directly addresses the NHMRC Strategic Initiative on Nanotechnology and Health, by providing essential information for designing safer nanomaterials from systemically studying the immune effects of metal oxide nanoparticles used in Australian industry.
Ion channels are complex proteins that regulate salt transport in cells. We have previously cloned, and have been studying, an unusual ion channel called CLIC1, whose function is uncertain. Recent data suggests it is located in areas of white cells that are involved in regulating inflammation and mice lacking CLIC1 are protected from some immune disorders. We wish to determine the role and mechanisms whereby CLIC1 regulates immune and inflammatory responses.