Regulation Of A Novel Target Gene, Aldehyde Dehydrogenase 1, By HOX11 In Childhood Leukaemia
Funder
National Health and Medical Research Council
Funding Amount
$382,027.00
Summary
Leukaemia is the most common cancer of childhood. Patients with the T-cell form of this disease (T-ALL), often carry specific chromosomal abnormalities that result in the activation of genes specifying transcription factors (TF's). TF's determine which genes are expressed in any given cell type, but when present in the wrong cell type at the wrong time may initiate cancer due to the combined activity of target genes under their control. The identification of target genes involved in cancer is th ....Leukaemia is the most common cancer of childhood. Patients with the T-cell form of this disease (T-ALL), often carry specific chromosomal abnormalities that result in the activation of genes specifying transcription factors (TF's). TF's determine which genes are expressed in any given cell type, but when present in the wrong cell type at the wrong time may initiate cancer due to the combined activity of target genes under their control. The identification of target genes involved in cancer is therefore essential in order to understand the mechanisms by which TF oncogenes induce tumour growth. However, very few target genes of TF's implicated in T-ALL have been discovered. HOX11 is one example of a TF aberrently expressed in childhood T-ALL. Recently we have shown that a gene called ALDH1 is under the control of HOX11 in a model cell system and also during normal development. The proper control of ALDH1 expression is important to the cell because it functions in the conversion of vitamin A to retinoic acid, a signalling molecule that critically affects cell growth and development. A related gene called RALDH2, that is also involved in retinoic acid synthesis, has very recently been shown to be under the control of other TF's implicated in T-ALL. These two discoveries therefore suggest that this disease may occur via a common pathway involving altered retinoic acid signalling. This project seeks to find out whether ALDH1 is also a target of HOX11 in T-ALL and if so, what effects it has on the cell. It also aims to determine how HOX11 influences the expression of ALDH1 and whether there are any other genes controlled by HOX11 that may be involved in tumour development. HOX11 provides an ideal model system to study the events leading to cancer that occur as a result of abnormal control of gene expression. Ultimately, such studies may lead to a better understanding of our normal biology as well as provide the basis for the design of improved cancer therapies.Read moreRead less
Understanding The Role Of The Essential Regulator WalKR In Staphylococcus Aureus
Funder
National Health and Medical Research Council
Funding Amount
$555,239.00
Summary
Staphylococcus aureus is one of the most common human bacterial pathogens. This project aims to characterise an important global control system in S. aureus, and determine if chemical inhibitors of this control system could be used to treat S. aureus disease in the future.
Targeting Homeobox Genes In Acute Myeloid Leukaemia
Funder
National Health and Medical Research Council
Funding Amount
$658,739.00
Summary
Acute myeloid leukaemia (AML) is a common blood cancer with dire clinical prognosis due to a lack of targeted molecular therapies. In this proposal we will identify new ways of targeting transcription factor proteins that are overexpressed in AML and promote leukaemia by repressing normal cellular growth controls. This may lead to novel methods to target leukaemic stem cells to specifically eliminate myeloid leukemia
Characterisation And Modelling Of Schizophrenia-associated Dysregulation Of MiR-137 Expression
Funder
National Health and Medical Research Council
Funding Amount
$581,661.00
Summary
We have identified mutation-associated changes in the expression of a non-coding microRNA gene in the cerebral cortex in schizophrenia. This gene, known as MIR137, functions by repressing hundreds of target genes and therefore has major implications for schizophrenia. The project will identify the genetic mechanism affecting the expression of MIR137, and determine the biological and behavioural implications of this change in the context of schizophrenia.
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.
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
Identifying Target Genes For Novel Anti-epileptic Therapies In The Mouse
Funder
National Health and Medical Research Council
Funding Amount
$469,802.00
Summary
Epilepsy is a disease which affects 2-4% of the population. There are a wide range of drugs available to treat the condition but there is consistently 30-40% of patients who do not respond well to any of these drugs and who continue to have seizures. The reason that there are no drugs available for these people is that most of the drugs available have been designed along the same principles. A new set of principles is needed to develop new drugs which will be able to treat those people not respo ....Epilepsy is a disease which affects 2-4% of the population. There are a wide range of drugs available to treat the condition but there is consistently 30-40% of patients who do not respond well to any of these drugs and who continue to have seizures. The reason that there are no drugs available for these people is that most of the drugs available have been designed along the same principles. A new set of principles is needed to develop new drugs which will be able to treat those people not responding to current therapy. This project is designed to identify new biologic pathways which may be interrupted with drugs to prevent seizures in people with epilepsy. This project uses a procedure to induce mutations into genes in mice and then screens for mice which do not seize when challenged with a drug which generates seizures in mice. Genetic studies will identify the mutated genes and these will be used as potential targets for new therapies or will identify new biological pathway which should expand the use of future anti-epileptic drugs.Read moreRead less
Improving Outcomes For Women Diagnosed With Mucinous Ovarian Cancer
Funder
National Health and Medical Research Council
Funding Amount
$598,238.00
Summary
Mucinous ovarian cancer (MOC) is different from other ovarian cancers but few studies have characterized the genetic changes specific to this subtype. It is often confused with metastases from other organs and does not respond well to standard ovarian cancer therapies. If MOC is more similar to mucinous cancers from other organs than other ovarian cancers, it may be better treated with chemotherapeutics that show success with other mucinous tumours.
Identification Of New Mutations That Contribute To Breast Cancer
Funder
National Health and Medical Research Council
Funding Amount
$323,825.00
Summary
Breast cancer affects approximately one in ten women and is therefore a major health problem. In order to improve the diagnosis, treatment and prognosis of this disease, it is critical to understand the genetic defects that contribute to disease initiation and progression. Although a number of breast cancer susceptibility genes have been identified, the contribution each of these genes makes to breast cancer susceptibility is currently unclear. This is partly due to limitations in current diagno ....Breast cancer affects approximately one in ten women and is therefore a major health problem. In order to improve the diagnosis, treatment and prognosis of this disease, it is critical to understand the genetic defects that contribute to disease initiation and progression. Although a number of breast cancer susceptibility genes have been identified, the contribution each of these genes makes to breast cancer susceptibility is currently unclear. This is partly due to limitations in current diagnostic processes and an incomplete understanding of all of the genetic elements for which disruption can lead to loss of gene function. This proposal aims to identify regulatory pathways that are critical for the expression of an important breast cancer gene called BRCA1. Furthermore, it aims to determine the status of these pathways in breast cancer patients, thus expanding our knowledge of the actual contribution that disruption of this gene makes to this disease. It also aims to determine the potential for trans-acting factors to regulate the expression of BRCA1 and thus activity of the BRCA1 pathway. The predicted outcome of this research is an improved ability to perform presymptomatic diagnostic testing for breast cancer and the ultimately the development of more effective drugs to treat certain breast tumours.Read moreRead less