Deciphering The Epigenetic Code Of T Lymphocyte Stability In Disease
Funder
National Health and Medical Research Council
Funding Amount
$662,785.00
Summary
T lymphocytes defend against invading pathogens and establish immunological memory to protect us if the infection returns. As there are many different types of pathogens, T lymphocytes must be flexible in the way they respond to infection but also stable once they have decided on the appropriate type of response. This complex decision-making appears to be dictated by epigenetic changes to the chromatin state of the cell. This work will uncover epigenetic factors that maintain this balance to pro ....T lymphocytes defend against invading pathogens and establish immunological memory to protect us if the infection returns. As there are many different types of pathogens, T lymphocytes must be flexible in the way they respond to infection but also stable once they have decided on the appropriate type of response. This complex decision-making appears to be dictated by epigenetic changes to the chromatin state of the cell. This work will uncover epigenetic factors that maintain this balance to protect us against disease.Read moreRead less
Epigenetic Signatures Of Abnormal Adult Neurogenesis In Rett Syndrome
Funder
National Health and Medical Research Council
Funding Amount
$869,332.00
Summary
Rett syndrome (RTT) is a severe neurodevelopmental condition arising in early childhood. In Australia, RTT affects an estimated 1/8500 females. The vast majority of RTT patients carry a single mutation in the gene MeCP2. Recent advances in genetic engineering may allow MeCP2 mutations to be corrected in patients. This study will assess whether other molecular factors are involved in the RTT phenotype in patient neurons, and whether these factors are likely to be corrected by MeCP2 gene therapy.
Epigenetic Predictors Of Outcome In Malignant Glioma
Funder
National Health and Medical Research Council
Funding Amount
$697,720.00
Summary
Human high grade gliomas (HGG) present as heterogeneous disease, primarily defined by the histologic appearance of the tumor cells.Glioblastoma multiforme (GBM) is the most common illness and continues to have a very poor prognosis, despite the use of multimodality therapy including surgery, radiation therapy and chemotherapy. We will use our existing biobank of specimens, clinical information and molecular investigation to identify factors that determine outcomes.
Essential Roles Of RNA Polymerase II Transcription And DNA Damage Response Pathway In The Maintenance Of Centromere Chromatin Assembly
Funder
National Health and Medical Research Council
Funding Amount
$601,224.00
Summary
A centromere is a region of DNA typically found near the middle of a chromosome where two identical sister chromatids come in contact. It is involved in cell division as the point of attachment to the mitotic spindle. Defective centromeres can result in genome instability, infertility and development of cancers. This work involves a study into how the identity of a centromere is maintained and inherited after each cell division. This has significant implication in the understanding of cell growt ....A centromere is a region of DNA typically found near the middle of a chromosome where two identical sister chromatids come in contact. It is involved in cell division as the point of attachment to the mitotic spindle. Defective centromeres can result in genome instability, infertility and development of cancers. This work involves a study into how the identity of a centromere is maintained and inherited after each cell division. This has significant implication in the understanding of cell growth and cancer development.Read moreRead less
Epigenetic Therapies To Differentiate And Eradicate Leukaemia Stem Cells
Funder
National Health and Medical Research Council
Funding Amount
$674,315.00
Summary
Leukemia stem cells (LSC) are often resistant to conventional and targeted therapies and therefore serve as the seed for leukaemia relapse. The overall aim of this project is to use small molecule therapies to block the activity of a particular protein (LSD1) in LSC in order to differentiate them and expose a vulnerability to another epigenetic therapy called a BET inhibitor. Together, these epigenetic therapies will differentiate and eradicate LSC, leading to improved outcome in AML.
Epigenetic Regulation Of Telomere Chromatin And Genome Stability
Funder
National Health and Medical Research Council
Funding Amount
$633,447.00
Summary
Telomeres are structures at the end of the chromosomes that impact cell replication. 15% of cancers, called ALT cancers, show telomere instability, increased DNA damage and are frequently mutated for the ATRX gene. ALT cancers have poor prognosis, due to the limited understanding of ALT cancer activation. This study aims to create a model of ALT activation to uncover the mechanisms that control ALT tumourigenesis. This could lead to potential ALT-specific diagnostic and therapeutic tools.
Chromosomal translocations in the MLL gene results in aggressive leukaemias. Several drugs developed to target proteins that interact with the MLL fusion proteins are now being tested in the clinic. Despite this progress, our understanding of how the MLL fusion proteins cause leukaemia remains incomplete. In particular, it is unclear how the MLL fusion protein drives the development of leukaemia. In this project I will address these important issues with cell and molecular biology methods.
Function Of ATRX, H3.3 And PML Nuclear Bodies In The Regulation Of Telomere Chromatin Integrity
Funder
National Health and Medical Research Council
Funding Amount
$434,652.00
Summary
The telomere is required for protecting chromosome ends. During cell division and development, telomeres lose their repeats, exposing the chromosome ends to damage. The consequences of this damage are disease, cancer, and aging. By contrast, embryonic stem cells (ES) continually renew their telomeres and do not stop growing. ES cells thereby provide a means to unravel the molecular mechanisms of indefinite telomere renewal. Here we propose a novel mechanism that operates to control continual tel ....The telomere is required for protecting chromosome ends. During cell division and development, telomeres lose their repeats, exposing the chromosome ends to damage. The consequences of this damage are disease, cancer, and aging. By contrast, embryonic stem cells (ES) continually renew their telomeres and do not stop growing. ES cells thereby provide a means to unravel the molecular mechanisms of indefinite telomere renewal. Here we propose a novel mechanism that operates to control continual telomere renewal in ES cells.Read moreRead less
Exploring DNA Methylation As A Mechanism For Long-term Memory For Fear Extinction
Funder
National Health and Medical Research Council
Funding Amount
$415,322.00
Summary
Traumatic experiences are well remembered. In some cases, fear-related memories become debilitating and require therapeutic intervention to diminish the impact of these kinds of memories on daily living. Such therapies engage a process of inhibitory learning called fear extinction. Since anxiety disorders are particularly sensitive to relapse even after extensive exposure therapy, a deeper understanding of the extinction process is crucial if we are to develop more effective treatment protocols ....Traumatic experiences are well remembered. In some cases, fear-related memories become debilitating and require therapeutic intervention to diminish the impact of these kinds of memories on daily living. Such therapies engage a process of inhibitory learning called fear extinction. Since anxiety disorders are particularly sensitive to relapse even after extensive exposure therapy, a deeper understanding of the extinction process is crucial if we are to develop more effective treatment protocols for a variety of anxiety disorders.Read moreRead less
Uncovering New Epigenetic-based Regulatory Mechanisms Of Gene Expression: Novel Links Between Histone Variants, RNA Function And Disease
Funder
National Health and Medical Research Council
Funding Amount
$1,053,671.00
Summary
It is estimated that greater than 90% of human genes undergo alternative RNA splicing, which can explain how protein diversity is achieved with a limited number of genes. However, how alternative splicing patterns are established remains poorly understood but is an important question given that 15-50% of human disease mutations are associated with changes to the splicing patterns of RNA. We have uncovered a new splicing mechanism, which involves changing the way DNA is packaged in a cell.