Genomic Characterisation Of Novel Inflammatory Regulators In A Mouse Model Of Disseminated Candidiasis
Funder
National Health and Medical Research Council
Funding Amount
$581,427.00
Summary
Genome biology offers great promise for the study of immune function, but new approaches are needed to build insights between data and disease. This project looks at the gene products used by mice susceptible to yeast infection and asks if the information is used differently in resistant animals. Blood-borne fungal infections are increasing in hospitals; we want to discover new immune gene products and understand how they contribute, so we can better predict the outcome of an infection.
Statistical Methods For Identifying Structural Variation In Tumour Genomes Using Next Generation Sequencing
Funder
National Health and Medical Research Council
Funding Amount
$243,458.00
Summary
New DNA sequencing technology can sequence a tumour genome affordably in 2 weeks. This re-sequencing data can be used to find small mutations and large-scale chromosomal rearrangements that together are the drivers of cancer. These may one day be used to guide cancer therapy. This project will develop new algorithms for finding mutations and apply these to discover the genetic basis of drug resistance in a model lymphoma system.
Combined Expression Analysis And SNP-based Measurement Of Copy Number Variation In Ovarian Cancer.
Funder
National Health and Medical Research Council
Funding Amount
$440,124.00
Summary
For a woman with advanced ovarian cancer, the degree and duration of her response to platinum agents is probably the single most important determinant of her chance of survival for an extended period. At the moment we cannot accurately predict that response and, despite a great deal of effort, we don't understand what controls her initial response to treatment and almost inevitable relapse with platinum-refractory disease. In recent years it has become possible to measure the patterns of activit ....For a woman with advanced ovarian cancer, the degree and duration of her response to platinum agents is probably the single most important determinant of her chance of survival for an extended period. At the moment we cannot accurately predict that response and, despite a great deal of effort, we don't understand what controls her initial response to treatment and almost inevitable relapse with platinum-refractory disease. In recent years it has become possible to measure the patterns of activity of thousands of genes simultaneously using microfabricated devices known as microarrays. As aberrant gene activity is a major determinant of tumour growth and drug sensitivity, we expect that such information will provide an insight into the dynamics of tumour growth and lead to tests that are predictive of treatment response and survival. Indeed, there are now a number of examples of solid cancers where microarray-based expression information is predictive of outcome and in breast cancer such information is being actively developed as a clinical tool. Our proposed research is based on the Australian Ovarian Cancer Study (AOCS), which is a national study established in January 2003 through a US Department of Defense CDMRP-OCRP Program grant. In just over 24 months AOCS has become the largest study of its kind in the world and represents a powerful bioresource for the molecular analysis of ovarian cancer. The objective of this application is to extend microarray analysis of AOCS serous ovarian cancer cases, particularly focusing on women with primary and acquired platinum resistance. Platinum resistance is the major barrier to long-term remissions in women with ovarian cancer. High-resolution genomic analysis of a large number of well-selected cases with linked outcome data should provide an extremely valuable molecular dataset for ovarian cancer.Read moreRead less
How Does Basal Chromatic Structure Predict Cytokine Gene Responses?
Funder
National Health and Medical Research Council
Funding Amount
$521,961.00
Summary
To recognise foreign pathogens and eradicate them from the body, immune cells need to quickly switch on genes encoding factors which communicate between cells and drive the immune response. Incorrect expression of these genes contributes to immune diseases such as asthma, arthritis and leukaemia. The aim of this project is to study how the DNA environment of immune genes controls their ability to be switched on and off, and how altering this environment leads to incorrect gene expression.
Mechanisms By Which Chromatin Modulates Gene Expression.
Funder
National Health and Medical Research Council
Funding Amount
$267,750.00
Summary
Gene expression in a cell occurs in the nucleus where genes are stored. In the nucleus, DNA is not in a free form but is covered with an equivalent weight of protein to form a structure known as chromatin. Chromatin is a periodic structure made up of repeating, regularly spaced subunits, the subunit being the nucleosome. A nucleosome consists of a group of proteins (histones) wrapped around with DNA. A nucleosome is both capable of blocking and activating gene expression. Therefore one important ....Gene expression in a cell occurs in the nucleus where genes are stored. In the nucleus, DNA is not in a free form but is covered with an equivalent weight of protein to form a structure known as chromatin. Chromatin is a periodic structure made up of repeating, regularly spaced subunits, the subunit being the nucleosome. A nucleosome consists of a group of proteins (histones) wrapped around with DNA. A nucleosome is both capable of blocking and activating gene expression. Therefore one important function of chromatin is to tightly regulate gene expression which is essential to allow an organism to develop properly. When gene expression is not accurately controlled by chromatin developmental defects or cancer can result from the production of incorrect proteins. To control correct gene expression, highly specific mechanisms must operate in the cell to remove, or modify, nucleosomes at certain genes at a precise time during development. One mechanism that we believe to be important is changing the make-up of a nucleosome. This can be achieved in the cell by the replacement of histones with different specialized forms of these histones (variants). We believe that these histone variants can specifically generate chromosomal domains which could in some cases expose or in other cases hide certain genes and thereby turn them on or off. Employing a new approach, we will study one of these histone variants to discover the role it plays in determining the type of chromosomal domain made and the role of this domain has in turning genes on or off at precise times in early development during the formation of different specialized cell types. This new information may define targets for the prevention of incorrect gene expression during cancer progression or abnormal development.Read moreRead less
Role Of NF-kB Recruited SWI/SNF Chromatin Remodeling Complexes In Inducible Gene Expression In T Cells
Funder
National Health and Medical Research Council
Funding Amount
$243,500.00
Summary
The immune system consists of a group of cell types, including T cells, which are capable of recognising foreign agents and eradicating them from the body. T cells are activated by foreign antigen and respond by producing an array of soluble factors including cytokines, which act as communicators between cells. The correct expression of these factors is critical for the maintenance and function of the immune system, and is therefore tightly regulated. The genes encoding these factors are general ....The immune system consists of a group of cell types, including T cells, which are capable of recognising foreign agents and eradicating them from the body. T cells are activated by foreign antigen and respond by producing an array of soluble factors including cytokines, which act as communicators between cells. The correct expression of these factors is critical for the maintenance and function of the immune system, and is therefore tightly regulated. The genes encoding these factors are generally maintained in an 'inactive' state but are switched on rapidly when required. Within the cell, genes or DNA are found wrapped up in a complex protein structure called chromatin which plays an important role in regulating gene expression. Chromatin forms a barrier to active gene expression which must be overcome before the gene can be switched on. There are protein complexes within the cell that are able to alter or remodel chromatin structure from an 'inactive' to an 'active' state. We are investigating one of these chromatin remodeling complexes to determine which genes it is able to switch on and how it targets these particular genes. Aberrant gene expression within T cells contributes to a range of diseases including certain leukemias and inflammatory conditions such as asthma and rheumatoid arthritis. Understanding the events and protein complexes involved in switching on specific genes in T cells will potentially identify molecules which can be targeted in an effort to control inappropriate gene expression in these disease states.Read moreRead less
Epigenomic Marks As Indicators Of The Kinetics Of Gene Activation In Immune Cells.
Funder
National Health and Medical Research Council
Funding Amount
$619,805.00
Summary
Switching on an immune response involves major changes in the gene expression program of the immune cells. These changes in gene expression take place in the context of DNA packaged into the nucleus in a structure known as chromatin. We will investigate the relationship between chromatin and gene expression changes and how this relationship plays a role in the timing of the immune response. This information will be useful in developing novel means of controlling aberrant immune responses.
Structural And Functional Analysis Of A Cancer-linked Co-regulator Complex
Funder
National Health and Medical Research Council
Funding Amount
$555,892.00
Summary
We seek to understand the mechanisms by which genes are switched on and off throughout our lifetime. A number of multi-component protein machines are involved in this process but their make-up and mechanism of action is not understood. We will investigate the structure and function of one of these machines that has been strongly linked to cancer.