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.
A DENDRITIC SUBSTRATE FOR THE CHOLINERGIC CONTROL OF NEOCORTICAL OUTPUT
Funder
National Health and Medical Research Council
Funding Amount
$898,340.00
Summary
The forebrain cholinergic system controls neocortical activity and cognitive function. This project will investigate the mechanisms by which the cholinergic system controls neocortical circuit activity in rodent models using advanced optical and electrical recording methods. The results will provide a foundation for the understanding of how dysfunction of the cholinergic system results in cognitive decline in humans, and identify new targets for improved treatment of human cognitive impairment.
Multi-centre, Multi-disciplinary Study Using A Systems Biology Approach To Investigate Immunomodulation In Children With Acute Wheeze
Funder
National Health and Medical Research Council
Funding Amount
$1,895,107.00
Summary
The concept that immunomodulation using naturally-occurring bacterial agents can treat asthma has reached international prominence. This is backed by strong epidemiologic and clinical trial data. However, detailed knowledge of the immunological mechanisms involved is essential to allow more focused therapeutic agents to be developed. The proposed multi-disciplinary immunomodulation study in 200 children aims to provide this essential information using an advanced systems biology approach.
The Differential Contribution Of Programmed Death-1 Ligands To Malarial Immunity
Funder
National Health and Medical Research Council
Funding Amount
$327,784.00
Summary
This research aims to understand how the Malaria parasite, which causes one of the world’s deadliest diseases, evades immunity. It will provide a significant advance in our knowledge of immunity against malaria and impact on current strategies to develop an efficacious vaccine or treatment for malaria.
P2X7 Mediated Phagocytosis Of Apoptotic Cells: A Common Mechanism Underlies Neurological And Eye Disorders
Funder
National Health and Medical Research Council
Funding Amount
$527,033.00
Summary
We have found a strong genetic linkage between a protein called P2X7 and a number of neurological disorders, in line with our recent discovery of a novel function of this protein in clearance of dying cells as removal of unhealthy neurons is essential to keep brain function promptly. Further study using genetic association, cell biology and animal models will lead to a conceptual advance on how neurological diseases are occurred and developed.
Molecular Basis For The Efficient Processing Of Antigens Taken Up By Clec9A, A DAMP Receptor On Dendritic Cells
Funder
National Health and Medical Research Council
Funding Amount
$1,302,392.00
Summary
Dendritic cells (DC) of the immune system utilise specific receptors to sense danger signals from their environment. We identified a DC danger receptor, Clec9A, which recognizes and induces immunity to “dangerous” dead cells eg. infected cells or killed tumour cells. We will investigate how DC use Clec9A to process “dangerous” dead cells, and the factors that control the potency of this immune response. This will enable us to develop novel immunotherapies for infectious diseases and cancer.
Disruption To Intracellular Trafficking As A Central Pathogenic Mechanism In Amyotrophic Lateral Sclerosis (ALS)
Funder
National Health and Medical Research Council
Funding Amount
$688,157.00
Summary
There are several different forms of ALS (MND), but the disease appears very similar in terms of symptoms and pathology. We have identified a common disease process shared by several different forms of ALS, which suggests that this is the underlying mechanism by which motor neurons die. This study will investigate whether we can develop new drug targets based on this mechanism in animal disease models. This may ultimately assist in the development of new treatments for ALS.
Glucose Toxicity-induced Activation Of The Bcl-2-regulated Apoptotic Pathway In Pancreatic Beta Cells
Funder
National Health and Medical Research Council
Funding Amount
$617,238.00
Summary
High blood glucose or hyperglycaemia is a feature of type 2 diabetes. Hyperglycaemia and fatty acids in the blood can cause damage of the insulin-producing pancreatic beta cells, resulting in worsening of diabetes. We plan to elucidate the pathways in beta cells that are stimulated by high levels of glucose and fatty acids, and to determine if these pathways are turned on in the pancreas of patients with type 2 diabetes, to try and identify targets for new therapies.
The Role Of Cytokines In Tumor-induced Immunosuppression
Funder
National Health and Medical Research Council
Funding Amount
$754,473.00
Summary
Cancer-induced immune suppression is a major obstacle to the effective treatment of many cancers. We have shown that the cytokine IL-23, plays an important role in cancer initiation, growth and development. My project aims to characterize the cells that produce IL-23 in the cancer microenvironment and define how it suppresses cells of the immune system. A greater understanding of this cytokine’s mechanism of action will enable the rational improvement of treatments for patients with cancer