SiRNA Induced TGS Of Retroviruses: Elucidation Of Underlying Mechanisms And Their Application In Animal Models
Funder
National Health and Medical Research Council
Funding Amount
$371,502.00
Summary
AIMS To elucidate changes in DNA that accompany suppression of HIV growth caused by certain unusual RNA molecules that turn off the ability of HIV to reproduce and make the virus dormant within the infected cell. While we have discovered RNA molecules that can do this to HIV in the test tube, we wish to develop similar molecules that can be used in animal models, so that we can decide whether this technology can be developed for use in humans. We also wish to understand more clearlky the mechani ....AIMS To elucidate changes in DNA that accompany suppression of HIV growth caused by certain unusual RNA molecules that turn off the ability of HIV to reproduce and make the virus dormant within the infected cell. While we have discovered RNA molecules that can do this to HIV in the test tube, we wish to develop similar molecules that can be used in animal models, so that we can decide whether this technology can be developed for use in humans. We also wish to understand more clearlky the mechanisms underlying this effect. BACKGROUND These RNA molecules can suppress a range of pathogenic human viruses including HIV-1 in the test tube. Our novel approach appears to induce changes that are long lasting and are less susceptible to mutations by the virus that allow it to become resistant to other therapeutic strategies. RESEARCH PLAN Initially more work will be done in tissue culture to determine the optimal design of these molecules and the best way to administer them. The most promising of these designs will be tested in small groups of infected animals as a preliminary demonstration of efficacy. In parallel experiments will be performed to elucidate the mechanisms undelying the suppressive effects of these molecules. OUTCOMES AND SIGNIFICANCE This work will lead to a significant increase in our understanding of the way replication of HIV is regulated and will develop a promising new therapeutic strategy for this virus that may be applicable to other conditions.Read moreRead less
Ecto-nucleoside Triphosphate Diphosphohydrolases Of Leishmania: Role In Virulence And Potential As Antimicrobial Targets
Funder
National Health and Medical Research Council
Funding Amount
$314,658.00
Summary
Leishmaniasis is a serious disease that affects millions of people worldwide, particularly in developing countries. The disease is caused by a number of species of parasites, and current treatment regimes are not ideal. This research aims to target certain proteins produced by the parasite and define the role of the proteins in causing disease. Furthermore this research will identify new drugs that will block these parasite proteins and may contribute to new therapies for this serious disease.
Functional And Structural Studies Of A Glycosyltransferase Essential For Complex Glycolipid Biosynthesis In Mycobacteria
Funder
National Health and Medical Research Council
Funding Amount
$508,838.00
Summary
Tuberculosis (TB) kills more than three million people each year while the causative bacterial species, Mycobacterium tuberculosis, infects one-third of the entire human population. An alarmingly high rate of TB exists in Australia's indigenous population. This proposal aims to identify and characterise essential processes involved in synthesis of the outer coat of the bacterium which are potential targets for new drugs for the treatment of this devastating disease.
Processes Underlying Establishment And Maintenance Of The Latent HIV Resevoir And Potential Impact Of Integrase Inhibitors
Funder
National Health and Medical Research Council
Funding Amount
$318,044.00
Summary
Therapy for HIV-infected individuals is currently able to control the growth of the virus, but cannot eradicate the viral infection. This is due to a pool of CD4+ T lymphocytes which contain HIV DNA in a latent state, ready to reactivate as soon as therapy is interrupted. This project aims to better understand how this pool of latently infected CD4+ T lymphocytes is established and maintained, particularly how it is linked to the essential T cell survival signal from interleukin 7.
Targeting The Mannose Activation Pathway In Leishmania - Novel Drug Targets And Vaccines.
Funder
National Health and Medical Research Council
Funding Amount
$338,661.00
Summary
Leishmaniasis is a parasitic disease ranging in severity from skin lesions to fatal systemic infection. It is a serious public health problem throughout many regions of the world. Co-infection with HIV has emerged as a serious problem in Africa, South America and southern Europe. Recently, leishmaniasis has been identified in East Timor and in kangaroos in Australia. Treatment of leishmaniasis is based on chemotherapy, but currently used drugs are expensive, have high toxicity and unwanted side ....Leishmaniasis is a parasitic disease ranging in severity from skin lesions to fatal systemic infection. It is a serious public health problem throughout many regions of the world. Co-infection with HIV has emerged as a serious problem in Africa, South America and southern Europe. Recently, leishmaniasis has been identified in East Timor and in kangaroos in Australia. Treatment of leishmaniasis is based on chemotherapy, but currently used drugs are expensive, have high toxicity and unwanted side effects. They have also been compromised by the emergence of resistance in the parasite. Leishmania synthesises a range of surface molecules, which are needed for virulence and parasite survival in the host. The biosynthesis process of these molecules requires activated mannose. We have identified two novel parasite genes encoding for enzymes, which are essential for the biosynthesis of surface virulence factors. When either of these genes is deleted the parasite can no longer cause disease. This suggests that drugs targeting the two enzymes will be able to control the infection. We will produce crystals of these enzymes and solve their 3D structure using state of the art technology to screen libraries of synthetic chemicals to find candidate inhibitors of enzyme activity. When these compounds are identified we will use computer modelling to design compounds based on these inhibitors and crystal structure, which will lead to a new generation of anti-Leishmania drugs. We will also determine whether the avirulent parasites can be used as an attenuated vaccine. Recovery from infection leads to a solid immunity and protection from subsequent infection indicating that vaccination is feasible, but despite of a huge amount of research there is no antileishmanial vaccine currently available. This study will lead to potential novel antileishmanial drugs and vaccines. It will also provide fundametal new knowledge of the structure of enzymes critical for parasite virulence.Read moreRead less
Novel Artemisinin-based Combination Therapies For Children Exposed To High Transmission Of Multiple Plasmodium Species
Funder
National Health and Medical Research Council
Funding Amount
$1,378,408.00
Summary
We recently found that the WHO-recommended combination antimalarial therapy artemether-lumefantrine and the candidate regimen dihydroartemisinin-piperaquine were not fully effective for both falciparum and vivax malaria in young PNG children, a group at risk of complications and death. We plan to study two new combinations (artesunate-pyronaridine and artemisinin-naphthoquine) and hypothesise that at least one will prove superior and be used as first-line treatment in PNG and similar countries.
Centre Of Research Excellence In Indigenous Children's Healthy EARs (ICHEAR)
Funder
National Health and Medical Research Council
Funding Amount
$2,615,897.00
Summary
The overwhelming burden of otitis media (middle ear inflammation, OM) and the consequences of hearing loss on social and educational outcomes in Indigenous children are indisputable. Our CRE_ICHEAR is a multidisciplinary group of Australia’s experts in OM research, policy and practice guidelines. The CRE will derive better value in terms of discovery, translation and sustainability. Increased Indigenous leadership will raise awareness and advocacy, with greater efficiency of research translation
Enhancing Clinical Management Of Paediatric Malaria In Endemic Areas With Transmission Of Multiple Plasmodium Species
Funder
National Health and Medical Research Council
Funding Amount
$867,511.00
Summary
Malaria remains a major problem for children in developing countries especially where different types of the disease are common. This set of complementary studies, based at an established research site in PNG aims to develop new treatment strategies for childhood malaria. A novel method of giving medicine via a spray under the tongue for sick children before arrival at hospital and modified dosing schedules of an old drug used for treating parasites hidden in the liver will be studied.
Risk Factors, Mechanisms, And Treatment Of Knowlesi Malaria
Funder
National Health and Medical Research Council
Funding Amount
$265,138.00
Summary
The monkey parasite P. knowlesi is an increasing cause of human malaria in SE Asia. My studies on the clinical epidemiology, diagnosis and treatment of non-severe and severe malaria in Malaysia have changed policy. I will further define the clinical epidemiology of malaria patients in this area over time, assess risk factors for knowlesi malaria, and evaluate the role of human and parasite factors in disease severity, and treatment for reducing acute kidney injury in knowlesi malaria.