Signaling Pathways To Enhance Potency Of AMPK-targeting Drugs
Funder
National Health and Medical Research Council
Funding Amount
$661,966.00
Summary
Sedentary lifestyles and consumption of high energy foods has led to epidemics of obesity-related metabolic diseases that place enormous financial and medical burden on the Australian economy. An attractive drug target to treat these diseases is AMP-activated protein kinase (AMPK) which functions as both a cellular fuel gauge and co-ordinator of whole-body metabolism. Our goal is to improve AMPK drug potency by identifying novel processes that sensitize AMPK to drugs.
A New Function For An Old Enzyme: Src Protein Kinase Directs Excitotoxic Neuronal Death In Stroke
Funder
National Health and Medical Research Council
Funding Amount
$513,975.00
Summary
In our previous investigation of how brain cells die in patients suffering from stroke, we found that stroke causes aberrant activation of an enzyme called Src in the affected brain cells. Furthermore, this aberrantly activated Src directs the brain cells to undergo cell death. Our proposal, which aims to decipher this neurotoxic mechanism of the aberrantly activated Src will benefit development of new therapeutic strategies to reduce brain damage in stroke patients.
Regulation Of Ca2+/calmodulin Dependent Protein Kinase Kinase-2 By Phosphorylation
Funder
National Health and Medical Research Council
Funding Amount
$570,334.00
Summary
This project will study the regulation of an enzyme called CaMKK2, which plays a pivotal role in controlling a number of important biological functions including brain development, regulation of appetite, energy metabolism and blood pressure. Understanding how this enzyme is regulated may open new avenues for treating Type 2 diabetes, obesity, and cardiovascular disease.
Validating CaMKK2 As A Rational Treatment Target For Bipolar Disorder
Funder
National Health and Medical Research Council
Funding Amount
$688,175.00
Summary
Bipolar disorder is a disabling, chronic mental illness that profoundly impairs the ability of affected individuals to function in daily life. Existing treatments for bipolar disorder are inadequate and lack the necessary efficacy and tolerability required for long-term therapy. This project will validate the enzyme, CaMKK2, as a rational treatment target for bipolar disorder, which will guide the development of more effective and safer drugs to improve patient outcomes.
What Is The Molecular Mechanism Underlying Cell Death By Necroptosis?
Funder
National Health and Medical Research Council
Funding Amount
$653,742.00
Summary
Recently, we and others have demonstrated that part of the MLKL protein is able to kill cells. This process is known to cause a number of pathologies, including those arising from stroke. Blocking this type of cell death has thus emerged as an attractive therapeutic strategy. However, precisely how MLKL kills cells remains unclear and controversial. In this project, we will resolve these controversies with the goal of an increased fundamental understanding to aid drug discovery.
The dramatic increase in obesity and age-related metabolic disorders demonstrates the importance of gaining a better understanding of how cells and organisms regulate their energy stores. This project will identify novel molecular mechanisms that control the enzyme CaMKK2, which is a key regulator of whole-body energy metabolism. This will provide new opportunities to inform more effective strategies to tackle metabolic diseases, and improve health in an increasingly ageing population.
This proposal investigates processes that regulate the cell cytoskeleton to control shape and the dynamics membranes, with a view to developing a generic antiviral therapy. As viruses rely upon the cell cytoskeleton to initiate an infection, we posit that enzymes that control the cytoskeleton can be targeted to block infection.
Assembly And Function Of Two Interacting Oncogenic Scaffolds
Funder
National Health and Medical Research Council
Funding Amount
$705,585.00
Summary
Aberrant signaling by the protein kinase superfamily is a known driving force for many cancers and inflammatory diseases. Recently, a subset of kinase-like proteins, termed pseudokinases, have emerged as crucial regulators of kinase signalling pathways. This proposal focuses on elucidating the scaffolding function and assembly of two pseudokinases, termed SgK223 and SgK269, which display oncogenic properties and aims to understand how their signalling abilities are subverted in a disease state.
Interactions Between RAGE And The Type 1 Angiotensin Receptor Determine The Pro-atherosclerotic Actions Of Angiotensin II
Funder
National Health and Medical Research Council
Funding Amount
$521,956.00
Summary
Heart attacks and strokes are a major cause of death and disability in Australians. Activation of the renin angiotensin system plays a key role in the development and progression of atherosclerosis, the process that leads to narrowing and obstruction of arteries. In preliminary data we have found a way to block these pathways without affecting the control of blood pressure. We believe that interventions based on these data will be important for the prevention and treatment of heart disease.
Spatial And Temporal Dimensions Of Mu-opioid Receptor Signalling: Implications For The Development Of Tolerance
Funder
National Health and Medical Research Council
Funding Amount
$799,316.00
Summary
The use of morphine as an analgesic is still limited by undesirable side effects such as tolerance. Despite decades of research, the mechanisms behind the development of tolerance are poorly understood. The ? opioid receptor is a protein expressed at the surface of the cells that is the target of morphine. This project will investigate the signalling events triggered by opioids with unprecedented resolution and will aim to elucidate why morphine elicits more tolerance than other opioid drugs.