SiRNA Induced Transcriptional Silencing Of HIV-1: Elucidating The Mechanisms And Exploring Options For Delivery
Funder
National Health and Medical Research Council
Funding Amount
$512,631.00
Summary
Current drug therapy for HIV is for life We have discovered a set of molecules that will turn off the ability of HIV to reproduce itself. These molecules are from a new family of RNA molecules . A single dose of these molecules suppress the ability of the virus to reproduce itself for more than a month. Further we have found ways of extending this supressive ability to greater than one year. These studies will tell us how these molecules work and how they might be effectively administered.
Mechanisms Of Propagation And Containment Of Gene Silencing
Funder
National Health and Medical Research Council
Funding Amount
$272,223.00
Summary
Long-term and heritable repression of genes by epigenetic mechanisms is essential for health but can also be dangerous if it goes wrong. Mathematical modelling and biochemical experiments will be used to understand how this gene silencing propagates and spreads along the DNA, and how it can be stopped from spreading too far.
Obesity-associated diseases are leading causes of death and are expected to increase as the obesity epidemic worsens. Because of the limited efficacy and/or safety concerns of currently available anti-obesity drugs, it is important to identify new drug targets. The results from this whole-genome scan will help to identify agents for obesity that reduce body weight and fat mass.
Solving Delivery Of Gene Therapy For Control Of Human Immunodeficiency Virus Infection
Funder
National Health and Medical Research Council
Funding Amount
$765,439.00
Summary
Antiretroviral therapy free control of Human Immunodeficiency Virus (HIV) infection requires control of the viral reservoir. We have a unique approach, aimed at enforcing HIV latency by targeting highly conserved regions in the viral promoter. These constructs completely silence viral transcription for long periods of time. We intend to develop & assess vectors that are specifically targeted to the reservoir and which can enforce viral latency despite immune activation or viral variation.
Variable Expressivity And Epigenetic Inheritance At The Axin Fused Locus In The Mouse
Funder
National Health and Medical Research Council
Funding Amount
$242,545.00
Summary
Genes influence the way we look and variations in gene sequence can account for the differences between individuals. Family traits are often credited to gene variants that are passed down through generations of families. There is now intriguing evidence, some coming from our laboratory, that gene sequence is not the only thing we inherit from our parents. Modifications that alter the expression but not the sequence of a gene, known as epigenetic modifications can, it turns out, be inherited in m ....Genes influence the way we look and variations in gene sequence can account for the differences between individuals. Family traits are often credited to gene variants that are passed down through generations of families. There is now intriguing evidence, some coming from our laboratory, that gene sequence is not the only thing we inherit from our parents. Modifications that alter the expression but not the sequence of a gene, known as epigenetic modifications can, it turns out, be inherited in mammals. An epigenetic modification is a mark, present on some genes that determines whether the gene is expressed (switched on) or silent. Animals are thought to acquire this mark during development and it is retained throughout life except in germ cells where the mark is generally, but not always, erased. The establishment of the mark appears to be a stochastic event at the cellular level resulting in mosaic expression. The percentage of marked cells can differ from one individual to another . In theory, this could help to explain why individuals with identical genetic information, such as identical twins, can have different phenotypic characteristics. The fact that these modifications can be inherited implies that there is an alternative mode of inheritance of genetic traits which does not involve mutation but which can be carried from generation to generation in a semipermanent way. Understanding the mechanisms underlying these events is important if we wish to predict or modify the phenotype of an invidual or that of his or her offspring.Read moreRead less
A FACS-based Screen For Retroviral Silencing: A Tool For Detecting Trans-sensing In Mammalian Cells
Funder
National Health and Medical Research Council
Funding Amount
$205,010.00
Summary
Retroviruses are RNA viruses that infect cells and then become integrated into the genome of the infected cell. This property has been exploited in attempts to cure genetic diseases by replacing the defective gene: the replacement can be incorporated into the retrovirus, transported into a cell, and become part of the cell?s genetic material. However, retroviruses are frequently suppressed by the host cell some time after integration, so that their genetic information becomes silent. The factors ....Retroviruses are RNA viruses that infect cells and then become integrated into the genome of the infected cell. This property has been exploited in attempts to cure genetic diseases by replacing the defective gene: the replacement can be incorporated into the retrovirus, transported into a cell, and become part of the cell?s genetic material. However, retroviruses are frequently suppressed by the host cell some time after integration, so that their genetic information becomes silent. The factors that cause silencing of retroviruses are not well understood, but it is clear that this problem is a major impediment to retrovirus-based (and perhaps all) gene therapies. In a wide variety of organisms, including plants, flies, and yeast, it has been found that multiple copies of a gene can silence each other, a phenomenon termed cosuppression. Some reports suggest that this might happen in mammals as well. We have initiated a study of retroviral silencing, using a marker protein that produces green fluorescence as a model for the replaced gene. We find that the gene is usually silenced after integration, immediately or over time, but can be reactivated by drugs that demethylate DNA or alter chromosomal structure. We now propose to extend this work by doing a systematic analysis of the frequency of retroviral silencing in human T cells, and then to develop a system to detect and analyze cosuppression by retroviruses. This work will rely on the ability of fluorescence-activated cell sorting (FACS) to detect rare events in a large population of cells, and recover those rare cells. We will also test methods of destabilizing the silent state of a retrovirus. These experiments are likely to yield information that will benefit a broad array of gene replacement efforts. A demonstration of cosuppression would be particularly interesting because of the possibility that endogenous elements in the mammalian genome are regulated by this mechanism.Read moreRead less
Targeting An Epigenetic Silencing Pathway To Treat Allergic Asthma
Funder
National Health and Medical Research Council
Funding Amount
$318,768.00
Summary
Asthma affects around 11% of the Australian population and costs the health care system around $28 billion. Unfortunately there is still no cure and treatments have not changed for decades. This project aims to discover new drugs to treat asthma by re-wiring the cells of the immune system which cause the disease.
Investigating The Role Of Novel Heterochromatin And Centromere Proteins In Chromosome Segregation
Funder
National Health and Medical Research Council
Funding Amount
$522,896.00
Summary
The equal division of genetic material during cell division is essential so that genetic material is not lost or gained. This process is controlled by a complex array of proteins that replicate the genome, maintain its structural integrity, and equally distribute one copy to each daughter cell. This research aims to study the functions of newly identified proteins required for this process in a single cell yeast model-system and in human and mouse cells.
Identification Of Variably Expressed Genes In Isogenic Mice And Humans
Funder
National Health and Medical Research Council
Funding Amount
$293,080.00
Summary
Monozygotic twins are known to have different phenotypic characteristics even though they contain identical genetic information. It is not uncommon for identical twins to have different coloured eyes and to show discordance for genetic diseases. While there is no definitive explanation for these differences they are generally thought to be caused by subtle changes in environmental conditions. We believe however, that these differences are set up during early embryonic development by the establis ....Monozygotic twins are known to have different phenotypic characteristics even though they contain identical genetic information. It is not uncommon for identical twins to have different coloured eyes and to show discordance for genetic diseases. While there is no definitive explanation for these differences they are generally thought to be caused by subtle changes in environmental conditions. We believe however, that these differences are set up during early embryonic development by the establishment of epigenetic modifications to the DNA. An epigenetic modification is a mark which determines whether a gene is expressed (switched on) or silent (switched off). The establishment of the mark appears to be a stochastic event which can result in different physical characteristics between genetically identical individuals. We would like to study this process in inbred mouse strains and in humans. Inbred mouse strains are maintained by inbreeding (brother-sister mating) to ensure that all individuals of the strain are isogenic (genetically identical) and in such a way that environmental variation is minimised. We will use established molecular techniques to find genes which are variably expressed among isogenic mice and humans. This work will enable us to discover genes which are sensitive to epigenetic modifications and whose epigenotype must be known if we are able to predict phenotype or disease state.Read moreRead less
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.