H2A.Z Acetylation: Deregulation Of Enhancer Activity And 3D Chromatin In Prostate Cancer
Funder
National Health and Medical Research Council
Funding Amount
$859,350.00
Summary
DNA is not linear but packaged in the cell nucleus in a three-dimensional (3D) structure in such a way that distal regulatory regions can interact to control gene expression. Our new data suggests that a chemical modification of the histone variant H2A.Z plays a critical role in the formation of the 3D chromatin structure. This project is aimed to dissect the role of H2A.Z in prescribing 3D structure, which will provide a more precise understanding of gene deregulation in cancer.
Genomic Analysis Of DNA Binding And Gene Regulation By The Chromatin Remodelling Factor UBF
Funder
National Health and Medical Research Council
Funding Amount
$624,254.00
Summary
Synthesis of ribosomes, the cellular protein synthetic machinery, is the major anabolic event of a growing cell and is frequently dysregulated during disease such as cancer. This grant will examine a protein termed UBF that we think plays an important role in orchestrating the cellular response to dysregulated ribosome biogenesis. By understanding how UBF functions we hope to uncover novel therapeutic approaches to treat diseases associated with ribosome stress .
The Role Of Nuclear Architecture In The DNA Damage Response
Funder
National Health and Medical Research Council
Funding Amount
$561,966.00
Summary
The goal of the proposed research is to understand how dynamic changes to the chromatin genome packaging network, interact with the DNA damage response and gene expression machinery, to repair damaged DNA and the impact this has on cancer biology. To do so we are combining cutting edge molecular biology techniques with innovative novel microscopy methods developed by our research team, that far exceed the spatiotemporal resolution currently used to study chromatin biology.
Regulation Of Ribosomal RNA Gene Chromatin During Malignant Transformation.
Funder
National Health and Medical Research Council
Funding Amount
$882,486.00
Summary
The overarching goal of this proposal is to determine the molecular basis for tumour cell dependence on activated ribosomal RNA gene repeats (rDNA). Our working model posits that rDNA repeats become activated through changes in rDNA chromatin structure that include increased binding of the RNA Polymerase I transcription factor UBF.
CTCF is a unique architectural protein that regulates the three-dimensional (3D) folding of the genome to switch our genes on, or off. This is important, as it affects how DNA is arranged inside the cells, which is turn assures correct gene expression patterns. Here, we will define the role of CTCF in organizing the 3D genome architecture and identify genetic and epigenetic states that control its function.
Four Dimensional Epigenome Remodelling: Implications For Endocrine Resistance In Breast Cancer
Funder
National Health and Medical Research Council
Funding Amount
$828,560.00
Summary
Patients with estrogen receptor positive breast cancer receive endocrine therapy, however half fail to respond and relapse. Endocrine resistant breast cancer currently represents the most significant challenge to breast cancer treatment. We suggest that three-dimensional epigenetic remodelling is an underlying mechanism that determines endocrine sensitivity that we will exploit as a novel therapeutic strategy to effectively treat patents with recurrent disease.
ManagemenT Of ChronIc CardioMetabolic DiseasE And Treatment DiScontinuity In Adult ADHD PAtieNts (TIMESPAN)
Funder
National Health and Medical Research Council
Funding Amount
$499,613.00
Summary
The aim of TIMESPAN is to improve the management of patients with Attention Deficit Hyperactivity Disorders (ADHD) and co-occurring cardiometabolic disease (i.e. obesity, type-2 diabetes, and cardiovascular disease). Inadequate treatment of these common conditions can lead to premature death and substantial societal costs. We will use linked electronic health records and novel research methods to improve clinical outcomes and quality of life of adults with ADHD and cardiometabolic disease.
A Clinical Trial To Determine The Optimal Timing Of Androgen Deprivation In Relapsed Or Non-curable Prostate Cancer
Funder
National Health and Medical Research Council
Funding Amount
$627,600.00
Summary
The aim of the study is to clarify when is the optimal time to start hormone treatment for men with certain stages of prostate cancer. It has long been known that testosterone removal impedes prostate cancer growth, although not permanently. The removal of testosterone, however, has side effects , including loss of libido, hot flushes, weight gain, and in the longer term osteoporosis, loss of muscle bulk and mental changes such as loss of memory. Any benefit to be gained for a patient must there ....The aim of the study is to clarify when is the optimal time to start hormone treatment for men with certain stages of prostate cancer. It has long been known that testosterone removal impedes prostate cancer growth, although not permanently. The removal of testosterone, however, has side effects , including loss of libido, hot flushes, weight gain, and in the longer term osteoporosis, loss of muscle bulk and mental changes such as loss of memory. Any benefit to be gained for a patient must therefore be weighed against these side effects. This is particularly relevant in situations in which cure is not possible, when the aim of treatment should be to manage symptoms (either by preventing or delaying them or treating them as they arise). There are two situations in which a man may be diagnosed as having active prostate cancer but be without symptoms requiring immediate treatment. The first is after the failure of curative treatment, shown by the presence of prostate specific antigen (PSA) in the blood, but without any other evidence of prostate cancer. The second is a man newly diagnosed with asymptomatic prostate cancer, but with other reasons (such as heart disease) which make an attempt at cure inappropriate. We do not know in either case whether or not men live longer if treatment is started immediately, or whether it is reasonable to wait until symptoms develop, thus potentially postponing the side effects of treatment. The trial will therefore include these two groups of men. Half the men will be randomised to receive immediate treatment, and half to treatment starting when symptoms develop, or when there is evidence of progressive disease. The main endpoint is overall survival, balanced against quality of life and side effects from the disease and treatment. The hypothesis is that early treatment will improve survival with acceptable effects on quality of life.Read moreRead less
A NOVEL MOUSE MODEL TO INVESTIGATE THE MECHANISMS OF VIRUS-INDUCED ARTHRITIS
Funder
National Health and Medical Research Council
Funding Amount
$336,000.00
Summary
We have developed a novel animal model by which to study arthritic disease caused by insect-transmitted viruses known as arboviruses. The existence of this model and novel reagents provides an excellent opportunity to further explore the basic mechanisms of infectious disease in a complete functioning animal, rather than specific cultured cells. The study will use modern approaches in molecular and cellular biology to achieve this goal. The production by our immune systems of soluble mediators ( ....We have developed a novel animal model by which to study arthritic disease caused by insect-transmitted viruses known as arboviruses. The existence of this model and novel reagents provides an excellent opportunity to further explore the basic mechanisms of infectious disease in a complete functioning animal, rather than specific cultured cells. The study will use modern approaches in molecular and cellular biology to achieve this goal. The production by our immune systems of soluble mediators (cytokines-chemokines) and antibodies is an overwhelming positive aspect of our physiological response to infection by microbes. Protection from disease by these immune compounds can happen naturally, or the body's ability to produce these factors can be exploited to our benefit via the administration of vaccines. However, these factors can also be detrimental to the host contributing to severe disease. For instance, work performed almost 40 years ago showed for the first time that under particular conditions, antibodies against viruses can enhance infection, instead of inhibiting infection as normally seen. In the intervening years work by scientists all over the world has associated antibody-dependent enhancement (ADE) of infection to many types of viruses; ADE is even thought to be a risk factor to serious disease with dengue virus, and has been shown in vitro for the AIDS virus and Ebola virus. We have recently discovered a molecular mechanism which explains how antibody enhances viral infection in vitro. In studies on immune cells infected with Ross River Virus (RRV) we found that infection helped by antibody resulted in the specific disruption to the production of cellular chemicals which are toxic to viruses. Are these mechanisms of antibody-enhanced infection also found in animals? Will such mode of infection cause enhanced disease and tissue pathology (arthritis) in animals?Read moreRead less