Substance abuse is a significant social and economic burden upon Australian societies and on societies around the world. Treatment remains problematic due to the multi-layer nature of the disease, difficulties with treatment compliance and less than ideal treatment regimes. The present study aims to improve treatments for alcohol and drug abuse using pre-clinical models to identify and characterize a new brain system implicated in drug-seeking.
High Penetrance Deleterious Mutations In Blinding Glaucoma
Funder
National Health and Medical Research Council
Funding Amount
$1,345,055.00
Summary
This project aims to identify the genes most commonly mutated in individuals with advanced glaucoma. Identification of such genes will lead to improved understanding of glaucoma pathogenesis, a better ability to predict risk, and the identification of drug targets for novel therapies.
Salt (sodium) is an essential electrolyte. Our convincing and complementary findings provide compelling evidence for a link between evolutionarily ancient “instincts” and substance abuse. This proposal is translational, including studies in opiate dependent humans. Our studies will establish how and where in the brain endogenous opioids are implicated in the gratification of salt appetite, how salt appetite is altered in opiate dependency and if salt appetite recovers following opiate withdrawal
Elucidating The Mechanism Of Action Of Dendrimer Nanoparticles Against HIV
Funder
National Health and Medical Research Council
Funding Amount
$559,354.00
Summary
Dendrimers are nanoparticles with highly branched structures and they are being developed as topical microbicides to prevent the sexual transmission of HIV. This study will determine how dendrimers block HIV entry into host cells so that we can design more effective inhibitors and microbicides.
Pathogenesis Of Persistent Human Virus Infections Of Global Significance
Funder
National Health and Medical Research Council
Funding Amount
$6,571,328.00
Summary
The study will investigate why humans cannot eradicate particular viruses (HIV-AIDS, cytomegalovirus and herpes simplex virus), the long term effects of these viruses and ways to improve control. Current treatments can only partly suppress the levels of these viruses, because they persist in certain parts of the body called reservoirs, only to resurge later causing disease. Thus, the overall aim of the research program is to discover the mechanisms by which these viruses are able to successfully ....The study will investigate why humans cannot eradicate particular viruses (HIV-AIDS, cytomegalovirus and herpes simplex virus), the long term effects of these viruses and ways to improve control. Current treatments can only partly suppress the levels of these viruses, because they persist in certain parts of the body called reservoirs, only to resurge later causing disease. Thus, the overall aim of the research program is to discover the mechanisms by which these viruses are able to successfully persist within reservoirs in the human body. The research program brings together a group of 6 leading scientists and clinicians located at 3 sites in 2 Australian cities. The team is comprised of experts in the study of HIV-AIDS, cytomegalovirus and herpes simplex virus who will combine their knowledge and expertise to speed up the process of research on these viruses that are of major health importance. Studies will also utilise a number of cutting edge technologies that now make it possible to much more rapidly and precisely determine how viruses cause disease. Advances in our understanding of how viruses persist may form the basis for treatments aimed at controlling persistent infections and the serious diseases caused by these viruses.Read moreRead less
The Role Of Chemokines In Establishing HIV Latency
Funder
National Health and Medical Research Council
Funding Amount
$372,049.00
Summary
Although antiviral therapy is effective in controlling HIV, therapy must be continued life-long because the virus cannot be cleared from long lived infected CD4+ T cells that are silently or latently infected. In this proposal we will explore the mechanism of how HIV can enter these resting CD4+ T-cells and establish long lived latent infection. Understanding this process may potentially lead to new strategies to cure HIV infection.
Mechanisms Underlying APOBEC3G Restriction Of HIV-1
Funder
National Health and Medical Research Council
Funding Amount
$540,075.00
Summary
In the fight against worldwide HIV-AIDS, understanding natural cell defenses to the HIV virus may identify new virus targets and strategies to block HIV in humans. Here, we will use state-of-the-art, high resolution, fluorescent microscopy to understand how the recently identified cell protein, APOBEC3G, blocks the HIV life cycle in human cells. We anticipate that APOBEC3G will stop HIV from invading the nucleus of human cells to defend against HIV, a strategy we can apply to new therapies.
The Role Of GRHL-3, A Mammalian Homologue Of Drosophila Grainyhead, In Neural Tube Development
Funder
National Health and Medical Research Council
Funding Amount
$496,500.00
Summary
Spina bifida and anencephaly are two common human congenital malformations that form part of a wide spectrum of mutations known collectively as neural tube defects (NTDs). Patients with the most severe form of spina bifida have a failure of the vertebral column and skin to close over the spinal cord and therefore suffer from limb paralysis and marked bladder and bowel dysfunction. Infants with anencephaly have an open cranial vault and failure of normal brain development and die within the first ....Spina bifida and anencephaly are two common human congenital malformations that form part of a wide spectrum of mutations known collectively as neural tube defects (NTDs). Patients with the most severe form of spina bifida have a failure of the vertebral column and skin to close over the spinal cord and therefore suffer from limb paralysis and marked bladder and bowel dysfunction. Infants with anencephaly have an open cranial vault and failure of normal brain development and die within the first few hours of life. These abnormalities occur frequently (1-1000 live births) and are a direct result of failure of the neural tube to close during embryogenesis. NTDs are influenced by both environmental and genetic factors. The best characterised environmental factor is the dietary supplement folate, which when administered before conception results in a reduction in the incidence of spina bifida. The genetic complexity is evidenced by the array of mouse genetic mutations that give rise to NTDs. One of these mouse mutations, known as Curly tail (ct), has served as the major animal model of human NTDs. This is because the ct mice are resistant to folate administration (like most of the cases of spina bifida currently seen in patients) and because the mice seem to have normal development in virtually all other organ systems. Ironically, the genetic mutation that causes the curly tail phenotype has remained undiscovered for over 50 years. We have now identified the gene mutated in the curly tail mice. This gene is highly conserved in humans suggesting that it will play a similar role in neural tube development in man. The gene, known as GRHL-3, is a descendant of a fly gene critical for development of the nervous system in that organism. The studies we propose here will examine the developmental pathways involved in normal neural tube closure in mice and humans and will impact on our understanding of these devastating congenital malformations.Read moreRead less
IMPROVING STROKE OUTCOMES: NEW TARGETS AND THERAPIES
Funder
National Health and Medical Research Council
Funding Amount
$7,212,064.00
Summary
Previously we established a unique collaboration of researchers from the basic and clinical sciences.. The main aim of this ' vertically integrated ' model was to develop new therapies to improve stroke outcomes. We developed a system to identify ' off-the-shelf ' compounds which protect the brain after stroke onset. This involves data assimilation (meta-analysis) in a unique way, an approach which has attracted attention internationally. We are also completing an important clinical trial using ....Previously we established a unique collaboration of researchers from the basic and clinical sciences.. The main aim of this ' vertically integrated ' model was to develop new therapies to improve stroke outcomes. We developed a system to identify ' off-the-shelf ' compounds which protect the brain after stroke onset. This involves data assimilation (meta-analysis) in a unique way, an approach which has attracted attention internationally. We are also completing an important clinical trial using the clot dissolving agent tPA to extend the time during which the drug may be effective beyond the three-hours currently used. In the next phase of our program we plan to expand the basic science component to identify parts of brain cells (axons and dendrites) which may yield important information about new drugs to protect the brain. We will use our novel summary data technique to test drugs in animal models more appropriate to the human stroke paradigm than have been used in the past In clinical studies we will follow our theme of identifying new targets for therapy using sophisticated PET and MRI imaging techniques, both in patients who are at great risk of stroke recurrence after a minor warning stroke and those with stroke caused by bleeding within the brain. These studies will provide information about predictors of recurrent and worsening stroke which may be modified by new therapies. The final stage in identifying new therapies is the Phase III clinical trial. We will complete one of these in which the most appropriate drug preventing further strokes in a major new stroke subtype will be identified. Toward the end of the program, we will commence phase 3 studies of drugs we have selected as being most likely to protect the brain based on our animal experiments. The main benefit of this unique collaborative research model is to efficiently identify new therapies to reduce the burden of stroke, currently the second most common cause of death globally.Read moreRead less