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Loss of insulin-producing beta cells leads to type 1 diabetes and rejection of allogeneic islet transplants. The aim of this program is to discover ways of protecting beta cells from damage. We will do this by investigating whether blocking crucial regulators of cell death can protect mouse and human beta cells from destruction in vitro and in vivo. In doing so, we aim to prevent diabetes in mice and potentially improve the survival of islet grafts after transplantation.
Targeting CD4-positive Cells For Anti-HIV Gene Therapy
Funder
National Health and Medical Research Council
Funding Amount
$356,646.00
Summary
Treatment of HIV early following infection is thought to be important for maximising the quality of life of patients. Conventional therapy has had some success in early intervention but resistance invariably develops. This application proposes to develop a gene therapy approach to elimiate HIV infected cells by introducing a suicide gene into those cells that harbor the virus. The advantage of this approach is the limited toxicity that is associated with gene therapies as well as the ability to ....Treatment of HIV early following infection is thought to be important for maximising the quality of life of patients. Conventional therapy has had some success in early intervention but resistance invariably develops. This application proposes to develop a gene therapy approach to elimiate HIV infected cells by introducing a suicide gene into those cells that harbor the virus. The advantage of this approach is the limited toxicity that is associated with gene therapies as well as the ability to target specific cell-types. It is proposed to genetically modify a strain of adenovirus to introduce a gene that will kill cells that it infects that also contain HIV. This is a novel approach and potentially may be an important treatment in the future. Anti-HIV gene therapy may also be useful in addition to the more conventional treatments.Read moreRead less
In type 1 diabetes the body becomes deficient in insulin production from pancreatic b cells because the immune system mistakenly attacks and destroys b cells as if they were an invading infection. Recurrence of autoimmune destruction of b cells also occurs following transplantation of whole pancreas or islet cells and may occur in the future when other engineered insulin producing cells are transplanted. The focus of this program is to better understand how b cells are killed by the immune syste ....In type 1 diabetes the body becomes deficient in insulin production from pancreatic b cells because the immune system mistakenly attacks and destroys b cells as if they were an invading infection. Recurrence of autoimmune destruction of b cells also occurs following transplantation of whole pancreas or islet cells and may occur in the future when other engineered insulin producing cells are transplanted. The focus of this program is to better understand how b cells are killed by the immune system and to test ways of protecting beta cells from these mechanisms. Because of the inaccessibility of the pancreas to study (particularly biopsy) in humans with diabetes, much of the proposed work will be carried out in b cells derived from non-obese diabetic (NOD) mice, the best available mouse model of type 1 diabetes. It is clear from the literature that a molecule called perforin found in cytoxic T lymphocytes (CTL) is a major, if not the major, mechanism the immune system uses against b cells. For this reason we will try to better understand the interaction between b cells and perforin and ultimately design ways of them from perforin-mediated cell death. It is equally clear that there are other mechanisms besides perforin that can cause b cell death and the program will also address discovery of these mechanisms and new ways to block them. Beta cells in NOD mice will be protected from perforin or other mechanisms by the addition of protective genes or removal of harmful genes using transgenic knockout technology. Addition or removal of genes involved in cell death can be done systematically and each protocol tested using NOD mouse model. The process of cell death that b cell undergo in type 1 diabetes is called apoptosis. Apoptosis is a general mechanism by which cells of all types die. Experts in the biology of apoptosis and perforin are important members of the program, providing the opportunity to translate the latest advances in cell death research to diabetes. This research addresses several of the specific research areas of interest to JDRF. It focuses on the prevention of b cell death in individuals with type 1 diabetes receiving islet transplants. It may be applicable in the future to protection of stem or precursor cells that have been differentiated into b cells or even to devising strategies to prevent the development of diabetes.Read moreRead less
Reducing Deaths From Pesticide Poisoning - Establishing A Regional Toxicology Research Centre.
Funder
National Health and Medical Research Council
Funding Amount
$739,727.00
Summary
The World Health Organization estimates suggest nearly half a million people die from acute pesticide poisoning in the Asia-Pacific region each year. The Sri Lankan project will be the first attempt to systematically test whether a range of strategies can reduce long-term neurological damage and deaths from pesticides. The Australian-Sri Lankan Collaboration will, over the next five years, aim to improve assessment of sub-acute and long-term morbidity; promote 'evidence-based' treatment; develop ....The World Health Organization estimates suggest nearly half a million people die from acute pesticide poisoning in the Asia-Pacific region each year. The Sri Lankan project will be the first attempt to systematically test whether a range of strategies can reduce long-term neurological damage and deaths from pesticides. The Australian-Sri Lankan Collaboration will, over the next five years, aim to improve assessment of sub-acute and long-term morbidity; promote 'evidence-based' treatment; develop new antidotes (and assess their cost effectiveness), and see if pesticide regulation can reduce the rate of severe or fatal poisoning. If successful, this program may become a model for the region as to how to substantially reduce this largely hidden tragedy.Read moreRead less
Use Of The Norfolk Island Genetic Isolate For Disease Gene Mapping
Funder
National Health and Medical Research Council
Funding Amount
$978,500.00
Summary
This gene mapping study will use a unique founder effect population to investigate two major public health disorders. We aim to identify genes that play a role in migraine and in cardiovascular disease, using a population from Norfolk Island. The Norfolk Island community is a population of ~1200 permanent residents, the majority of whom are direct descendents of 18th century English Bounty mutineers and Polynesian women. We will undertake a full genome scan to identify migraine gene loci and QTL ....This gene mapping study will use a unique founder effect population to investigate two major public health disorders. We aim to identify genes that play a role in migraine and in cardiovascular disease, using a population from Norfolk Island. The Norfolk Island community is a population of ~1200 permanent residents, the majority of whom are direct descendents of 18th century English Bounty mutineers and Polynesian women. We will undertake a full genome scan to identify migraine gene loci and QTL that influence cardiovascular disease using samples from this population isolate.Read moreRead less
Gene Based Treatment Strategies For Diabetic Retinopathy
Funder
National Health and Medical Research Council
Funding Amount
$2,630,000.00
Summary
Diabetic retinopathy is the leading cause of blindness in the working population of developed countries and it is an increasing problem in the developing world. Present therapy involves extensive laser destruction of the light-detecting part of he retina. In addition, it is not only effective when administered at an appropriate stage in the disease process. Consequently, there is an urgent need for the development of better, prophylactic, easily administrable and cheaper therapies. This project ....Diabetic retinopathy is the leading cause of blindness in the working population of developed countries and it is an increasing problem in the developing world. Present therapy involves extensive laser destruction of the light-detecting part of he retina. In addition, it is not only effective when administered at an appropriate stage in the disease process. Consequently, there is an urgent need for the development of better, prophylactic, easily administrable and cheaper therapies. This project aims to develop a potentially permanent solution to alleviate diabetes-related blindness in the world. The project combines several very recent scientific advances into one strategy to combat diabetic retinopathy at a molecular level. Vision is our most important sensory organ that cannot be replaced. Thus, human trials can only be conducted following extensive animal safety and efficacy trials. To date the development of new therapies has been seriously hampered by the lack of appropriate, easy to reproduce animal models for different stages of diabetic retinopathy. In addition, it aims to identify new therapeutic agents from molecules that are naturally produced by the retina while fighting the disease. Finally, tested and evaluated in the animal models. The most successful therapeutic candidates will then be further developed for human trials.If successful, our approach will potentially have a major impact on the treatment of diabetic retinopathy and possibly on all diabetic vascular diseases. A single injection might only be necessary to prevent the development of diabetic retinopathy, which would represent a significant weapon in the management of patients. In addition, successful application of secretion gene therapy in the eye might open up the possibility to introduce the same concept for the treatment of larger organs undergoing microvascular changes as a result of diabetes.Read moreRead less
Mapping Genes For Typical Migraine Using Twin Families.
Funder
National Health and Medical Research Council
Funding Amount
$439,124.00
Summary
Current evidence suggests multiple genes may underlie susceptibility to the more common forms of migraine. The project will look to see if the these genes provide clues to the further elucidation of the complex molecular pathways of migraine and will help in the development of diagnostic tests and evidence-based treatment strategies.
HIV infection of CD4+ lymphocytes leads to a high rate of reproduction of new virus. However, in the brain, HIV infection of the astrocytes does not yield high levels of new virus. HIV is genetically active in these astrocytes, producing high levels of the messenger molecules, the so-called mRNA, that code for the proteins required for a new virus particle. We have determined that these HIV mRNAs are specifically prevented from translating into protein. The mechanisms controlling protein transla ....HIV infection of CD4+ lymphocytes leads to a high rate of reproduction of new virus. However, in the brain, HIV infection of the astrocytes does not yield high levels of new virus. HIV is genetically active in these astrocytes, producing high levels of the messenger molecules, the so-called mRNA, that code for the proteins required for a new virus particle. We have determined that these HIV mRNAs are specifically prevented from translating into protein. The mechanisms controlling protein translation from RNA are relatively poorly understood compared with the other control points of cellular gene expression, such as the synthesis of mRNA. This project examines how astrocytes rapidly detect the presence of HIV mRNA and alter their translation machinery to halt the expression of HIV protein. This host defence mechanism involves two key components; the cellular component that identifies and responds to the viral mRNA, and the structural features of the HIV mRNA that enable the cell to detect its viral origin. We will study how translation of HIV proteins requires both HIV and cellular factors. We will determine the impact of both viral RNA elements and viral RNA binding proteins on the translation of viral and cellular proteins. The contribution of the type-1 interferons that are produced in response to viral infection will be studied for their role in augmenting the inhibition of HIV protein translation. Since HIV infected astrocytes significantly contribute to the onset of AIDS dementia, we will sees a strategy to lock HIV into a dormant state in the brain and thereby prevent the neurodegenerative disease associated with HIV. We will use the anti-viral mechanism blocking HIV protein translation in astrocytes to protect other cell populations, such as the CD4+ lymphocytes, from HIV infection. These studies will also give insights into the general mechanisms for translational control of gene expression in human cells.Read moreRead less