Approaches to combat AIDS and its causative agent, the human immunodeficiency virus HIV-1, have thus far proved ineffective. The proposed research program intends to investigate the nuclear import of two HIV-1 proteins which have central roles in HIV infection. We will apply our expertise in the area of the regulation of nuclear import of viral proteins, and build on our observations with respect to these proteins to attempt to establish the mechanistic basis of their nuclear import, and how thi ....Approaches to combat AIDS and its causative agent, the human immunodeficiency virus HIV-1, have thus far proved ineffective. The proposed research program intends to investigate the nuclear import of two HIV-1 proteins which have central roles in HIV infection. We will apply our expertise in the area of the regulation of nuclear import of viral proteins, and build on our observations with respect to these proteins to attempt to establish the mechanistic basis of their nuclear import, and how this differs from the conventional nuclear import pathways used by normal cellular proteins. We already have evidence that nuclear import of HIV-Tat is regulated in novel fashion by cellular factors, and intend, through determining its mechanistic basis, to be able to form the basis of a strategy to block this import pathway specifically, and thereby inhibit HIV replication. This may form the basis in the future of a new pharmaceutical approach to combat HIV-AIDS.Read moreRead less
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
Pathogenic Role Of MicroParticles In Cerebral Malaria
Funder
National Health and Medical Research Council
Funding Amount
$250,000.00
Summary
Cerebral malaria (CM) is a life-threatening complication of infection caused by parasites. The mechanisms leading to coma, convulsions and death in CM remain unknown. CM in children is associated with high levels of endothelial microparticles (MP). However, not only the levels but also the phenotypes of MP can be altered in CM as well as their related functional properties. The project aims to develop a better definition of the MP released during CM and to study MP phenotypes in relation to clin ....Cerebral malaria (CM) is a life-threatening complication of infection caused by parasites. The mechanisms leading to coma, convulsions and death in CM remain unknown. CM in children is associated with high levels of endothelial microparticles (MP). However, not only the levels but also the phenotypes of MP can be altered in CM as well as their related functional properties. The project aims to develop a better definition of the MP released during CM and to study MP phenotypes in relation to clinical syndrome, disease severity and disease outcome.Read moreRead less
Prevalence, Nature And Recommendations For Clinical Management And Self-management Of Depression For People With HIV
Funder
National Health and Medical Research Council
Funding Amount
$470,290.00
Summary
By comparing the nature and prevalence of depression in those with and without HIV, and documenting the ways in which general practitioners manage depression in their patients, the project will provide a comprehensive and layered understanding of depression among men, particularly those living with HIV in urban and regional Australia. Project findings will develop the skills and research capacity of general practitioners in the assessment and management of depression.
Derivation Of Pancreatic Beta Cells From Embryonic Stem Cells
Funder
National Health and Medical Research Council
Funding Amount
$2,968,050.00
Summary
People with type 1 diabetes require regular insulin injections because the organ that normally makes insulin, the pancreas, no longer functions. The goal of this program is to derive human fetal pancreas tissues from embryonic stem cells. Such tissue could be used to replace the missing insulin producing cells in people with type 1 diabetes. The program brings together expertise in ES cell biology at Monash University and the leading diabetes research at the Walter and Eliza Hall Institute.
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
Molecular Analysis Of Pathways In Diabetes (MAPDB) Study
Funder
National Health and Medical Research Council
Funding Amount
$3,348,000.00
Summary
The sequence of human genome provides a complete part-list of the genes and proteins that make our bodies. A most unknown subset of these parts work together in molecular pathways that underpin susceptibility and resistance to Type 1 diabetes and its complications. The MAPDB study will link patients, families, doctors, genome experts, immunologists, physiologists, statisticians and data base programmers together to illuminate these molecular pathways. In particular, the study will reveal genes a ....The sequence of human genome provides a complete part-list of the genes and proteins that make our bodies. A most unknown subset of these parts work together in molecular pathways that underpin susceptibility and resistance to Type 1 diabetes and its complications. The MAPDB study will link patients, families, doctors, genome experts, immunologists, physiologists, statisticians and data base programmers together to illuminate these molecular pathways. In particular, the study will reveal genes and pathways that medicate protection from diabetes and its complications - either by inhibiting T cell responses to pancreatic beta cells, protecting or regenerating beta cells in the face of metabolic or immunologic stress, or protecting eyes and kidneys from the damaging effects of high blood glucose. By identifying genes and proteins with these functions, the study will enable new treatments to be developed aimed at augmenting these protective pathways, to prevent diabetes starting in children at risk, and to preserve beta cell mass, protect transplanted stem cells or beta cells, and prevent eye and kidney damage in people already affected by Type 1 diabetes. Genes and proteins that are needed for T cell attack on beta cells will also be revealed. This information will enable new treatments to be developed that block these processes, to prevent diabetes from starting, to preserve beta cell mass and to prevent destruction of transplanted stem cells or beta cells. The MAPDB study will also identify different versions-alleles- of many of the genes in the pathways described above. Particular combinations of these gene alleles will be defines that can identify people at high risk of developing Type 1 diabetes, risk of cell or islet transplantation rejection, or at most risk for eye-kidney complications. Different gene combinations may be found that allow different kinds of Type 1 diabetes to distinguished. By creating ways to identify and distinguish people's individual risk, the study will yield diagnostic tests to enable new treatments and clinical trials to be targeted.Read moreRead less
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.
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