The Role Of NF-kB Transcription Factors In Regulating T Cell Transcription Networks
Funder
National Health and Medical Research Council
Funding Amount
$534,000.00
Summary
T cells are a key element of the adaptive immune response and help to distinguish between self and non-self. Hence, an inappropriate T cell response can lead to autoimmunity and chronic inflammatory disease. When T cells are activated by an immune signal they switch on the production of an array of proteins that control both T cell function and other arms of the immune system. The genes encoding these proteins possess molecular switches (promoters and enhancers) that respond to immune signals. T ....T cells are a key element of the adaptive immune response and help to distinguish between self and non-self. Hence, an inappropriate T cell response can lead to autoimmunity and chronic inflammatory disease. When T cells are activated by an immune signal they switch on the production of an array of proteins that control both T cell function and other arms of the immune system. The genes encoding these proteins possess molecular switches (promoters and enhancers) that respond to immune signals. These molecular switches bind groups of proteins known as transcription factors. One family of transcription factors that plays a key role in T cell function is the NF-kB family consisting of five different members, three of which are important in T cell function. Aberrant NF-kB function or expression has been associated with autoimmunity, chronic inflammation and cancer. In addition, NF-kB proteins are key components of transplant rejection. There is enormous interest in using the NF-kB pathway as a therapeutic target for these pathologies. We currently have a detailed knowledge of the biology of these factors through studies of mice lacking specific family members. While we know some of the genes that are switched on by the NF-kB proteins, we currently lack a sufficiently detailed knowledge of NF-kB-regulated genes in order to link the molecular function with the biological outcomes. In order to understand the molecular mechanism of NF-kB function and relate this to the biological outcomes, we need a global view of NF-kB action in the cell. This proposal uses both experimental and computational approaches to decipher the gene expression program controlled by NF-kB proteins in T cells. The T cell transcription networks in which NF-kB proteins participate will also be investigated. The knowledge generated by these experiments will provide a solid basis for designing therapeutic approaches based on the NF-kB pathway.Read moreRead less
Genomic Characterisation Of Asbestos Related Lung Cancer
Funder
National Health and Medical Research Council
Funding Amount
$88,099.00
Summary
Lung cancer causes more deaths in Australia than any other cancer. Smoking is the main cause, but people exposed to asbestos are also at risk, and it can be difficult to know whether a case is due to tobacco, asbestos or both. We will study lung cancer genes in people with asbestos exposure to find whether asbestos lung cancer has a specific pattern of abnormal genes (signature). If so, this could help people entitled to compensation, and also point to new treatments for asbestos lung cancer
Retrotransposon Regulation Of The Human Innate Immune Response
Funder
National Health and Medical Research Council
Funding Amount
$231,937.00
Summary
Complete sequencing of the human genome has revealed the positions of approximately 20,000 genes. In addition, nearly 50% of the human genome is comprised of repetitive sequences previously thought of as junk DNA. Numerous studies are now finding that this DNA actually has a variety of important functions, particularly in the control of gene activity. This project will examine the relationships between gene expression and nearby repetitive sequences during the innate immune response in humans.
Regulation Of Nuclear Calcium Concentration In The Life Or Death Of Cells
Funder
National Health and Medical Research Council
Funding Amount
$195,047.00
Summary
The nucleus is the most prominent of all cell organelles and contains the primary genetic material for cellular development and growth. It performs some of the most important functions in the life and death of all living cells. However, little is known about many of the regulatory signals and events that control nuclear function. We will use new genetically-encoded sensor molecules that a living cell can be instructed to produce at various internal locations to explore important features of cell ....The nucleus is the most prominent of all cell organelles and contains the primary genetic material for cellular development and growth. It performs some of the most important functions in the life and death of all living cells. However, little is known about many of the regulatory signals and events that control nuclear function. We will use new genetically-encoded sensor molecules that a living cell can be instructed to produce at various internal locations to explore important features of cell control. This study will look specifically at how changes in the concentration of ionised Ca2+ in the nucleus control the switching on of genes and the initiation of programmed cell death pathways. This information is of significance to our understanding of normal cell growth and development, as well as abnormal growth (e.g. cancer).Read moreRead less
Alternative Splicing Of GLI1 And Its Role In Tumourigenesis
Funder
National Health and Medical Research Council
Funding Amount
$392,640.00
Summary
Gene expression involves the transfer of information from DNA to proteins and is mediated by a third molecule called messenger RNA (mRNA). The process is tightly controlled since unregulated gene expression is harmful and can result in diseases such as developmental disorders and cancer. The genetic information in DNA is first copied to an RNA molecule in a process called transcription. This RNA molecule then undergoes a series of maturation steps before the information it carries can be transla ....Gene expression involves the transfer of information from DNA to proteins and is mediated by a third molecule called messenger RNA (mRNA). The process is tightly controlled since unregulated gene expression is harmful and can result in diseases such as developmental disorders and cancer. The genetic information in DNA is first copied to an RNA molecule in a process called transcription. This RNA molecule then undergoes a series of maturation steps before the information it carries can be translated into a protein. One of these maturation steps involves the removal of sequences (called introns) that do not contain protein coding information from the sequences (called exons) that will be present in the mature mRNA. Some genes contain no introns while others contain 20 or more, which are dispersed throughout the gene. The removal of intron sequences from immature RNA molecules is called splicing and is carried out by a macromolecular complex that recognises the intron sequences, cuts them out of the RNA and then rejoins the RNA to make a contiguous sequence. This process has to be precise otherwise spurious sequences will be present in the mRNA, which will result in the production of abnormal proteins. In addition, for some genes mRNAs are produced that have differences in a portion of their sequence. These alternative sequences are generated by the inclusion or exclusion of alternative exons. Because, RNA splicing is critical to the production of mature mRNAs and because it can generate sequence diversity it is tightly regulated. We have recently found that expression of a cancer gene (called GLI1) is regulated in part by the use of alternative GLI1 mRNAs. Moreover, we found that the expression of one of these alternative GLI1 mRNAs is associated with skin cancer. In this project we will investigate the molecular mechanisms that regulate alternative splicing in GLI1 and identify whether changes in these mechanisms result in cancer.Read moreRead less
The Role Of Epigenetic And Transcriptional Regulation In CD8+ T Cell Effector Gene Expression.
Funder
National Health and Medical Research Council
Funding Amount
$72,571.00
Summary
All cells contain DNA that is tightly wrapped around proteins, whereby changes in the structure allow for the expression of proteins. Cells of the immune system express proteins that can resolve viral infections. This study plans to examine the factors mediating the changes in DNA that allow for the expression of these proteins in immune cells. Insights will enable a greater understanding of how these proteins are generated and maintained, and hence will have implications for vaccine design.
HPV And Cervical Carcinoma: Signaling And Clinical Responses To Interferons
Funder
National Health and Medical Research Council
Funding Amount
$534,480.00
Summary
Cervical carcinoma and its treatment continues to be an important health concern in Australia. The interferons comprise an elaborate system of natural substances produced in the body, one of whose functions is to prevent cancer cells from developing. The interferons have been widely used to treat human diseases including viral infections and cancers caused by the wart virus. However, results of recent work indicates that viruses like the wart virus, HPV, have developed ways of inhibiting its eff ....Cervical carcinoma and its treatment continues to be an important health concern in Australia. The interferons comprise an elaborate system of natural substances produced in the body, one of whose functions is to prevent cancer cells from developing. The interferons have been widely used to treat human diseases including viral infections and cancers caused by the wart virus. However, results of recent work indicates that viruses like the wart virus, HPV, have developed ways of inhibiting its effectiveness. We have found that cervical carcinoma cells and virally infected cells resist the direct anti-cancer and anti-viral effects of interferons because they have abnormalities in their ability to respond to interferon. We have made good progress in understanding why these cells do not respond to the interferons. In particular they show a deficiency in the activity of cell proteins required to transmit the interferon signal inside the cells. The current proposal will allow us to gain a greater understanding of the processes inside cells that are taken over by the wart viral proteins and the reasons for its abnormality in interferon resistant cancer cells. We will determine whether the levels of certain genes in clinical samples from patients relates to their response to interferon treatment. This may allow us to establish a test to predict which patients will respond to interferon therapy, saving patients from ineffective treatment, side effects and cost. This study will have a broad significance to many human diseases where abnormalities in interferon signaling occur and will help to bring about the necessary changes in cell properties to overcome the abnormalities, restore the responses and improve the application of interferons to treat infectious diseases and perhaps other cancers as well.Read moreRead less
The Investigation Of Immune Function In Mice Deficient In RNA-binding Molecules.
Funder
National Health and Medical Research Council
Funding Amount
$419,737.00
Summary
Our immune system is delicately balanced between fighting off bugs and destroying infected cells yet protecting healthy cells within the body. The ways in which the immune system responds to attack is regulated by certain genes within the body. This project is focussing on cutting edge research that describes a newly identified way of fine-tuning the immune system. We are studying RNA-binding molecules that can bind to and block genes involved in immune function.
Investigating Widespread Regulation Of Gene Expression Through Intron Retention
Funder
National Health and Medical Research Council
Funding Amount
$363,026.00
Summary
We recently discovered a hidden type of gene regulation that appears to be altered in diverse cancers including leukaemia, melanoma and colon cancer. We will explore this widely relevant mechanism using molecular and computational tools. We created the only computer program able to detect this type of regulation and will now share our discovery with cancer scientists through cloud computing technology.