Exploiting And Defining The Immune Regulatory Activities Of BET Bromodomain Inhibitors
Funder
National Health and Medical Research Council
Funding Amount
$128,224.00
Summary
Immune-based agents such as “checkpoint inhibitors” have the ability to re-awaken our own immune systems and activate previously dormant anti-tumour responses. We have discovered that small molecule inhibitors of gene regulatory proteins called bromodomain proteins act synergistically with checkpoint inhibitors in mouse cancer models. I will define the molecular and biological events underpinning this novel combination approach and assess the effects of the combination across different tumours.
Modulation Of Apoptosis By Cytomegalovirus: Analysis Of New Mechanisms To Interfere With Cytomegalovirus-induced Disease
Funder
National Health and Medical Research Council
Funding Amount
$697,084.00
Summary
Apoptosis, or programmed cell death is an essential process in developmental and homeostatic control of complex biological systems. In addition to these primary house keeping roles, apoptosis provides a powerful defence mechanism against invading pathogens, such as viruses, since it allows early elimination of infected cells from the host. A basic property of herpesviruses is their ability to establish persistent infection and remain in association with the host for its lifetime. This strongly u ....Apoptosis, or programmed cell death is an essential process in developmental and homeostatic control of complex biological systems. In addition to these primary house keeping roles, apoptosis provides a powerful defence mechanism against invading pathogens, such as viruses, since it allows early elimination of infected cells from the host. A basic property of herpesviruses is their ability to establish persistent infection and remain in association with the host for its lifetime. This strongly underlines their success at reaching an accommodation with the immune system's anti-apoptotic mechanisms. The central hypothesis of this project is that herpesviruses, such as murine and human cytomegalovirus, encode proteins that interfere with cell death pathways thereby circumventing host defence so that viral replication and dissemination can proceed. Thus, the aims are to identify and characterise cytomegalovirus proteins that modulate apoptosis. These studies will improve our understanding of the control of apoptosis during viral infection, especially as caused by cytomegaloviruses. Human cytomegalovirus (HCMV) is a pathogen able to cause significant morbidity and mortality in individuals with immature or compromised immune systems, such as newborns, AIDS patients, transplant recipients and people treated with chemotherapeutic drugs. Hence, the proposed studies will allow the elucidation of molecular mechanisms that may be relevant to the pathogenesis of HCMV in man and will provide insights into the rational design of suitable antiviral drugs and vaccines. Understanding viral mechanisms of host immune evasion continues to improve our understanding of complex cellular pathways. Therefore, given that abnormal regulation of apoptosis is implicated in the development of degenerative conditions, cancer and autoimmune disease, the proposed studies will provide valuable insight towards the development of new therapies for these pathological conditions.Read moreRead less
Analysis Of The Functions Of A Novel Class Of Ubiquitin E3 Ligases In TNF Signalling In Vivo
Funder
National Health and Medical Research Council
Funding Amount
$568,861.00
Summary
The aim of this project to discover the role of a novel ubiquitin ligase complex that regulates TNF superfamily signalling. It will increase understanding of the TNF pathway and improve our ability to manipulate it pharmacologically, or otherwise, in the large number of debilitating human diseases including Rheumatoid Arthritis and Crohn's disease that result from aberrant TNF signalling. Because of the role of TNF in tumorigenesis it may also contribute to novel anti-cancer treatments.
Identifying The Critical Components Of Growth Factor-mediated Survival Pathways
Funder
National Health and Medical Research Council
Funding Amount
$589,338.00
Summary
The regulation of cell lifespan (cell survival) is controlled by growth factors and lies at the heart of all biological processes. However, little is known of the molecular switches inside cells that either turn survival on or off. We propose to identify and characterize the molecular switches inside cells that control the balance between cell survival and death. Targeting specific components of these switches may provide new approaches for the treatment of cancer and infectious diseases.
To study the genetic alterations that give rise to cancer. In particular, exploring how too little death of cells can lead to a tumour. If too few cells in a tissue die, a tumour may develop there. The team is exploring how the cell death process is normally controlled. They plan to characterise the molecules inside cells that determine whether a cell lives or dies and hope that better understanding of those molecules will help to explain how tumours arise. It could also lead to new drugs that c ....To study the genetic alterations that give rise to cancer. In particular, exploring how too little death of cells can lead to a tumour. If too few cells in a tissue die, a tumour may develop there. The team is exploring how the cell death process is normally controlled. They plan to characterise the molecules inside cells that determine whether a cell lives or dies and hope that better understanding of those molecules will help to explain how tumours arise. It could also lead to new drugs that can kill tumour cells more effectively by directly triggering the normal death switch of the cell.Read moreRead less
Assemble A Cross-disciplinary Team With Requisite Skill To Uncover New Molecular Pathways Regulating Haemopoiesis
Funder
National Health and Medical Research Council
Funding Amount
$2,448,475.00
Summary
The major preoccupation of biology in the last decade has been the sequencing of the genomes of humans and important animal, plant, bacterial and viral organisms. With the completion of these projects, focus has shifted to understanding the molecular networks that regulate the biochemical, cellular and physiological processes that maintain health and the changes to these networks that lead to the onset and progression of disease. Within this fluid research landscape, my principal career goal ove ....The major preoccupation of biology in the last decade has been the sequencing of the genomes of humans and important animal, plant, bacterial and viral organisms. With the completion of these projects, focus has shifted to understanding the molecular networks that regulate the biochemical, cellular and physiological processes that maintain health and the changes to these networks that lead to the onset and progression of disease. Within this fluid research landscape, my principal career goal over the next 5 years is to ensure that, during a period of generational change at WEHI, its iconic molecular haematology team continues to flourish. Realizing this goal will allow us to use knowledge of the molecular determinants of health and disease to improve clinical outcomes of poorly treated conditions and in doing so improve the lives of patients and the health of the Australian economy.Read moreRead less
TAF8 is a small protein that is associated with the general transcriptional apparatus. TAF8 is not an essential part of the general transcriptional machinery, but rather a regulatory molecule that appears to dictate how the machinery is used to express different genes. The absence of TAF8 leads to expression of genes controlling cell death. Since the avoidence of cell death is essential to the development of cancer these results will lead to a better understanding of how cancer develops.
Small Molecule Apoptosis Inhibitors To Define The Bak Activating Switch
Funder
National Health and Medical Research Council
Funding Amount
$713,687.00
Summary
Tissue loss due to excessive apoptosis is a contributing factor to organ transplant failure and other diseases characterised by too much cell death. Using an innovative cell-based screening approach, we have identified a first in class series of molecules that potently block cell death driven by the apoptosis effector Bak. By unravelling the molecular target of our unique inhibitors and characterising their mode of action, we hope to uncover a new facet of Bax and Bak biology.
Investigation Of Molecular And Cellular Determinants Of Immune Related Adverse Events Following Treatment With Immune Checkpoint Inhibitors
Funder
National Health and Medical Research Council
Funding Amount
$128,224.00
Summary
Novel immune-based treatments for advanced, incurable, cancer have significantly improved patient survival. Although these treatments have proven highly effective, they are associated with the unpredictable development of severe and sometimes life-threatening autoimmune disease. We aim to discover ways to predict and potentially prevent these complications by identifying genetic risk factors and markers in blood samples. If successful, this will be a ground breaking advance in cancer care.