Tropisetron: Molecular Mechanisms Of Action At The 5-HT3 Receptor And The Glycine Receptor
Funder
National Health and Medical Research Council
Funding Amount
$371,800.00
Summary
Tropisetron and related drugs are used clinically to combat chemotherapy-induced nausea and vomiting. These drugs are termed '5-HT3 antagonists' because they block the activity of 5-HT3 receptor ion channels, which are found in parts of the brain that control the vomit reflex. Tropisetron also has potent effects on the glycine receptor chloride channel, which inhibits the nervous system. Depending on the concentration used, tropisetron can either increase or decrease the activity of the glycine ....Tropisetron and related drugs are used clinically to combat chemotherapy-induced nausea and vomiting. These drugs are termed '5-HT3 antagonists' because they block the activity of 5-HT3 receptor ion channels, which are found in parts of the brain that control the vomit reflex. Tropisetron also has potent effects on the glycine receptor chloride channel, which inhibits the nervous system. Depending on the concentration used, tropisetron can either increase or decrease the activity of the glycine receptor. If a drug can be found to selectively increase glycine receptor activity, it may be useful as an analgesic. In this project, we aim to understand the molecular mechanisms by which tropisetron interacts with the 5-HT3 receptor and the glycine receptor. This may help to identify novel analgesic drugs and more selective anti-emetic drugs.Read moreRead less
Genome Wide Investigations Of Mycobacterium Tuberculosis To Reveal Processes Of Pathogenesis
Funder
National Health and Medical Research Council
Funding Amount
$396,341.00
Summary
Tuberculosis remains a global health burden of staggering proportions. Around 1 in 3 people are infected with Mycobacteria tuberculosis, the organism responsible for the disease, which kills 2 million people annually. The emergence of strains now resistant to almost all of our front line drugs has placed extra pressure on researchers who are attempting to develop new protective vaccines and the critical antibiotics required to eradicate the disease. Furthermore the current global HIV pandemic is ....Tuberculosis remains a global health burden of staggering proportions. Around 1 in 3 people are infected with Mycobacteria tuberculosis, the organism responsible for the disease, which kills 2 million people annually. The emergence of strains now resistant to almost all of our front line drugs has placed extra pressure on researchers who are attempting to develop new protective vaccines and the critical antibiotics required to eradicate the disease. Furthermore the current global HIV pandemic is making the situation far worse as HIV kills the very cells of the body that protect us from tuberculosis. This research project will fill the significant gaps in our knowledge of M. tuberculosis infection, specifically identify the genes of the organism which allow it to invade and spread throughout the body. M. tuberculosis infection consists of 3 characteristic stages, i.e. colonisation, spread and long term survival in specialised structures called granulomas. It is from these granulomas that the bacterium can emerge after long periods of inactivity to cause clinical tuberculosis. Using a mouse model of infection I will define the genes needed by the bacterium to survive at these 3 key stages of disease thereby providing for a better knowledge base from which to design new vaccine strategies and to create effective drugs.Read moreRead less
HCMV Protein Kinase And DNA Polymerase Domains Involved In Antiviral Sensitivity, Viral Replication And Cell Tropism
Funder
National Health and Medical Research Council
Funding Amount
$269,250.00
Summary
Many individuals with compromised immune systems - such as those with HIV-AIDS, cancer and transplant recipients are at risk of disease from human cytomegalovirus (HCMV) infection. Currently the most effective therapies are suppression of virus replication by continuing administration of antiviral agents, principally ganciclovir (GCV), cidofovir (CDV) or foscarnet (phosphonoformic acid or PFA). The use of antivirals for increasingly longer durations in an enlarging population of patients with ir ....Many individuals with compromised immune systems - such as those with HIV-AIDS, cancer and transplant recipients are at risk of disease from human cytomegalovirus (HCMV) infection. Currently the most effective therapies are suppression of virus replication by continuing administration of antiviral agents, principally ganciclovir (GCV), cidofovir (CDV) or foscarnet (phosphonoformic acid or PFA). The use of antivirals for increasingly longer durations in an enlarging population of patients with irreversible chronic immunosuppression, has resulted in the emergence of increasing numbers of drug-resistant HCMV viruses in this group of individuals. In patients with AIDS, 7.6% of isolates in one study were shown to be GCV resistant and we have found similar levels (10.8%) in immunosuppressed Australians. Of the small number of antiviral agents with any useful activity against HCMV, GCV, and aciclovir (ACV) are nucleoside analogues. PFA is a pyrophosphate analogue that competitively inhibits pyrophosphate binding by HCMV DNA polymerase. These drugs are activated by a specific gene of HCMV (UL97 (Pk)) and a mouse virus (MCMV - M97Pk) that is very similar to HCMV. The drug then acts on a second gene encoding the DNA polymerase (HCMV UL54 DP or MCMV M54DP) to prevent viral growth. We are investigating the resistance genotypes and phenotypes in CMV resistant to 7 antiviral drugs including GCV, CDV and PFA. We have shown new resistant genotypes and are currently determining the protein-functional correlates of the genotypic changes, in order to increase understanding of the PK and DP genes, define the genetic causes of resistance, and to produce better targets for antiviral agents.Read moreRead less
The Role Of The Gtf2i Gene Family In Behaviour And Williams Syndrome
Funder
National Health and Medical Research Council
Funding Amount
$629,396.00
Summary
Williams Syndrome (WS) is a complex neurodevelopmental disorder in humans caused by a deletion of 21 genes on chromosome 7. This results in a reduced IQ and marked visuospatial deficiencies. However, unlike other forms of mental retardation, some important cognitive abilities are completely normal. WS patients show normal development of linguistic abilities and anecdotal evidence suggests they possess an above average musical ability. In addition, these individuals also possess a characteristic ....Williams Syndrome (WS) is a complex neurodevelopmental disorder in humans caused by a deletion of 21 genes on chromosome 7. This results in a reduced IQ and marked visuospatial deficiencies. However, unlike other forms of mental retardation, some important cognitive abilities are completely normal. WS patients show normal development of linguistic abilities and anecdotal evidence suggests they possess an above average musical ability. In addition, these individuals also possess a characteristic overfriendly, gregarious personality with little inhibition towards strangers. Such a characteristic cognitive and behavioral profile in a genetic disorder has provided convincing evidence that genes play a role in specifying cognitive abilities and behavior. This interesting syndrome gives us an insight into the perplexing debate of Nature vs Nurture. It also provides a unique and invaluable opportunity to dissect the role of certain genes in complex neurodevelopmental pathways that result in cognition and behavior. Recently, patients with smaller (atypical) deletions of genes in the WS region have been described. These patients do not display the full 'classical' range of WS characteristics. The identification of which genes are deleted in these patients suggests that two genes in particular, GTF2IRD1 and GTF2I, are involved in visuospatial abilities, sociability and specific anxieties and phobias. Our laboratory was the first to identify proteins encoded by GTF2IRD1, known as MusTRDs, that act for the most part to suppress gene expression. Furthermore, our laboratory has been studying a mouse model in which the Gtf2ird1 gene has been deleted, similar to the situation in WS, and have found that the mice are more 'social' and exploratory. In this project, we want to determine if other behavioural features of WS are contributed to by this gene and-or its related gene, Gtf2i, and to characterize the role that these genes play in neuronal cell function.Read moreRead less
Molecular Definition Of Neural Pathways In The Embryo And Adult Mouse
Funder
National Health and Medical Research Council
Funding Amount
$401,000.00
Summary
It is our objective to gain insight into the role of the Stem Cell leukaemia (SCL) gene in the central nervous system (CNS). SCL is known to play a crucial role in blood cell development and if aberrantly expressed can lead to T-cell leukemia. Although we do know that SCL is expressed in the brain, its role in the CNS has not been addressed so far and it is of great interest to us to study its potential function in neural development. We have designed a series of experiment in mice to elucidate ....It is our objective to gain insight into the role of the Stem Cell leukaemia (SCL) gene in the central nervous system (CNS). SCL is known to play a crucial role in blood cell development and if aberrantly expressed can lead to T-cell leukemia. Although we do know that SCL is expressed in the brain, its role in the CNS has not been addressed so far and it is of great interest to us to study its potential function in neural development. We have designed a series of experiment in mice to elucidate the expression pattern of SCL in the CNS, to identify the phenotype of neural cells that express SCL in different regions of the mouse brain, and to ablate the SCL gene at different time points during life (during embryonic development, just after birth and during adulthood). These experiments will be performed in conditional transgenic mice that have unique and precisely defined genetic alteration and are generated by us specifically for our research on the SCL-gene. This genetic approach is used to define the neuroanatomical and molecular bases of SCL-function in the brain.Read moreRead less
Molecular Interactions Of Novel Conotoxin Inhibitors Of The Noradrenaline Transporter
Funder
National Health and Medical Research Council
Funding Amount
$392,036.00
Summary
A novel class of conotoxins (chi-conotoxins) has been discovered in the venom of an Australian cone snails, Conus marmoreus. Chi-conotoxins are the first peptide inhibitors of the noradrenaline transporter. From binding studies, it appears they act at a new site, remote from the site of action of antidepressants. This project is aimed at understanding how and where this novel class of peptide binds to the transporter. The results of this study are designed to maximise the potential of these pate ....A novel class of conotoxins (chi-conotoxins) has been discovered in the venom of an Australian cone snails, Conus marmoreus. Chi-conotoxins are the first peptide inhibitors of the noradrenaline transporter. From binding studies, it appears they act at a new site, remote from the site of action of antidepressants. This project is aimed at understanding how and where this novel class of peptide binds to the transporter. The results of this study are designed to maximise the potential of these patented peptides to be used as leads to the development of a new class of therapeutic for controlling the adverse effects of inadequate noradrenaline balance.Read moreRead less
Two Recently Identified Calcium Transporters In Lactation And During Mammary Epithelial Cell Apoptosis.
Funder
National Health and Medical Research Council
Funding Amount
$465,115.00
Summary
The transport of calcium into milk is a key event in human health. In addition to its importance in neonatal nutrition, the way breast cells regulate calcium also has implications in breast cancer, as well as the modification of proteins important in immunity, and the activity of biopharmaceuticals. This grant will determine how two specific calcium transporters regulate calcium levels in the breast and their respective roles in cellular processes important in normal function and in disease.