Making Signalling Through The Tumour Necrosis Factor Receptors Selective For Promoting Neutrophil Antimicrobial Activity
Funder
National Health and Medical Research Council
Funding Amount
$196,312.00
Summary
It is evident to the professional and general community that antibiotic and drug resistance displayed by bacteria is a continuing and growing problem in the treatment of infection with potentially casastrophic effect on the health of our community. This concern is only partly reduced by our potential to develop new antimicrobial agents and vaccines. If we were able to use immunomodulators in a relatively safe and appropriate manner to target and enhance the antimicrobial power of specific compon ....It is evident to the professional and general community that antibiotic and drug resistance displayed by bacteria is a continuing and growing problem in the treatment of infection with potentially casastrophic effect on the health of our community. This concern is only partly reduced by our potential to develop new antimicrobial agents and vaccines. If we were able to use immunomodulators in a relatively safe and appropriate manner to target and enhance the antimicrobial power of specific components of the immune system then this could be exploited in the treatment of infection. While body proteins formed (cytokines) which modify the behaviour of the immune system are being used as pharmaceuticals, their toxic side effects are problematic to the patient. Our project focusses on one of the cytokines, tumor necrosis factor (TNF), which increases the antimicrobial activity of phagocytic cells but in addition can have quite devastating effects on other tissues in the body. This is because when TNF binds to its receptor on cells and tissues it elicits a multitude of signals inside the cell which can also precipitate illness. The purpose of our investigations is to identify which signals are responsible for increasing resistance against infection and which are not. With this information we will then see if it is feasible to selectively stimulate this signal from outside the cell since this has a better chance of succeeding as a pharmaceutical. This task is likely to be achievable since our research team has made some unique observations about TNF signalling characteristics and we have developed a peptide TNF mimetic which shows only the characteristics of increasing antimicrobial activity.Read moreRead less
Site-specific Tau Phosphorylation To Treat And Understand Alzheimer’s Disease
Funder
National Health and Medical Research Council
Funding Amount
$943,902.00
Summary
Alzheimer’s disease (AD) is the most common form of dementia. Unfortunately, current therapies are ineffective. Our laboratory has made an important contribution to understanding the events that lead to brain cell malfunction in AD. I recently found a novel concept that changes the view of AD completely. In the next 3 years, I aim to develop therapeutic tools based on this novel concept and find out more about how it can protect brains from AD.
The Role Of ERK MAPKs In Compensated Cardiac Hypertrophy
Funder
National Health and Medical Research Council
Funding Amount
$241,650.00
Summary
According to recent statistics, heart failure accounts for almost 300 deaths each year in Australia. In fact, heart failure is now a major health problem that is on the rise, despite the reduced incidence of other forms of heart and blood vessel disease. We are now in the situation where the cost of treatment of heart failure exceeds that of treating all cancer patients, and there are more patient days in hospital with heart failure than with any other heart or blood vessel disease. Most often, ....According to recent statistics, heart failure accounts for almost 300 deaths each year in Australia. In fact, heart failure is now a major health problem that is on the rise, despite the reduced incidence of other forms of heart and blood vessel disease. We are now in the situation where the cost of treatment of heart failure exceeds that of treating all cancer patients, and there are more patient days in hospital with heart failure than with any other heart or blood vessel disease. Most often, the heart fails to act as an effective pump following long-term exposure to high blood pressure. The increased work load placed on the heart effectively forces it to increase in size in a process called cardiac hypertrophy. But this initial compensation which is of benefit to the patient commonly deteriorates and many of the heart cells die. The resulting death of heart cells is the failure of the heart, and death of the patient is inevitable. The fundamental changes in the functional protein molecules of the heart cells that accompany hypertrophy and heart failure are likely to be extremely complex. As yet, no research has taken a global and unbiased look into this complexity. However, there are new technologies that allow us to take such a look. We have established a collaborative research team to investigate the fundamental mechanisms underlying cardiac hypertrophy. We are exploiting a novel model in which hypertrophy does not progress to failure. Our combined expertise allows us to use recently developed scientific methodologies to evaluate the biochemical basis for these events in the heart. We have chosen to focus on documenting the changes in proteins that accompany cardiac hypertrophy with the aim to establish important targets for interventions to permit cardiac cells to survive despite hypertrophy. This will have important implications for preventing cardiac failure.Read moreRead less
Melanoma Resistance To Combination BRAF And MEK Inhibition Is Driven By Reprogramming Of MAPK Signaling
Funder
National Health and Medical Research Council
Funding Amount
$745,082.00
Summary
Until recently, patients with metastatic melanoma were treated with single agent chemotherapy drugs that produce response rates of less than 10%. New drugs targeting the mitogen activated protein kinase (MAPK) pathway have now shown significant activity, but nearly all patients treated with these new inhibitors eventually develop resistance and progress. This project utilises patient tumour samples to examine the mechanisms of resistance and ways of enhancing the targeted inhibition of the MAPK ....Until recently, patients with metastatic melanoma were treated with single agent chemotherapy drugs that produce response rates of less than 10%. New drugs targeting the mitogen activated protein kinase (MAPK) pathway have now shown significant activity, but nearly all patients treated with these new inhibitors eventually develop resistance and progress. This project utilises patient tumour samples to examine the mechanisms of resistance and ways of enhancing the targeted inhibition of the MAPK signaling cascade.Read moreRead less
New drugs targeting the immune system have dramatically improved the survival of melanoma patients. Nevertheless, 30-40% of patients responding to these new inhibitor will develop drug resistance. This project utilizes patient tumour samples to examine the mechanisms of acquired resistance to immune checkpoint inhibitors. This information will accelerate the identification of novel combination therapies to improve patient outcomes.
Manipulating Oncogene Addiction And Immunity In The Treatment Of Melanoma
Funder
National Health and Medical Research Council
Funding Amount
$687,975.00
Summary
Melanoma is a major Australian health problem and a common cause of cancer death in young adults. Treatment of melanoma has been revolutionised in the last few years, but many patients fail to respond to new therapies or rapidly progress on treatment. This proposal examines the mechanisms that drive resistance to therapy and identifies markers predictive of clinical response. This approach will accelerate the development of new strategies and improve patient care by personalising treatment.
MKP-1 As A Novel Anti-inflammatory Strategy In Asthma And Airway Remodelling
Funder
National Health and Medical Research Council
Funding Amount
$461,528.00
Summary
Asthma is a chronic disorder where airways are remodelled, or thickened, resulting in poor lung function. Airway remodelling is a consequence of long-term inflammation after multiple episodes of asthma. As the current drugs to treat remodelling have side effects, the aim of this grant is to investigate a novel anti-inflammatory strategy to reverse the development of airway remodelling by increasing the anti-inflammatory protein - MKP-1.
Protein Kinases Regulate Salt Reabsorption In The Kidney
Funder
National Health and Medical Research Council
Funding Amount
$531,696.00
Summary
This proposal is designed to determine how the kidney senses the level of salt in the body and monitors blood pressure. This is critical for diseases such as hypertension, kidney and heart failure, where salt is retained inappropriately. We propose that the kidney uses proteins called kinases that are activated by salt in the kidney. When it is too low, they detect this and cause the kidney to absorb more salt to correct the deficiency. The way that they are able to do this has profound implicat ....This proposal is designed to determine how the kidney senses the level of salt in the body and monitors blood pressure. This is critical for diseases such as hypertension, kidney and heart failure, where salt is retained inappropriately. We propose that the kidney uses proteins called kinases that are activated by salt in the kidney. When it is too low, they detect this and cause the kidney to absorb more salt to correct the deficiency. The way that they are able to do this has profound implications for human heart and kidney disease, and biology in general.Read moreRead less
Structure And Function Of The AMPK Glycogen-binding Domain
Funder
National Health and Medical Research Council
Funding Amount
$538,764.00
Summary
The AMP-activated protein kinase (AMPK) is an enzyme responsible for coordinating metabolism in response to energy supply (diet) and energy demand (exercise). Research into this kinase can increase our understanding of how diet and exercise are so important for maintaining health. The kinase acts either by sensing when cellular energy levels become too low for normal functioning or when the body tells it by sending a chemical messenger (hormone) that overall energy levels are low. This results i ....The AMP-activated protein kinase (AMPK) is an enzyme responsible for coordinating metabolism in response to energy supply (diet) and energy demand (exercise). Research into this kinase can increase our understanding of how diet and exercise are so important for maintaining health. The kinase acts either by sensing when cellular energy levels become too low for normal functioning or when the body tells it by sending a chemical messenger (hormone) that overall energy levels are low. This results in activation of energy-producing pathways and inhibition of energy-consuming pathways, allowing cells to match supply with demand to ensure their survival. The AMPK comprises of three proteins that together form a functional enzyme. I have previously found that AMPK localizes to a source of cellular energy called glycogen (sugar stores) via one part that I have called the glycogen-binding domain. In this application I aim to obtain a thorough understanding of the molecular basis of how the glycogen-binding domain affects AMPK function in muscle and heart following exercise. In addition this research may lead to the identification of new molecules, similar to glycogen, that are important for AMPK regulation and may lead to the development of a new class of drugs for Type 2 Diabetes. Research into AMPK promises to dramatically increase our knowledge of how to reduce the risk of cardiovascular and neurodegenerative diseases, diabetes and obesity and provide an understanding of the reasons these diseases develop.Read moreRead less
REGULATION OF PROTEIN KINASES AND THEIR SUBSTRATES
Funder
National Health and Medical Research Council
Funding Amount
$1,296,159.00
Summary
Protein kinases are important regulatory enzymes involved in the control of virtually all physiological processes at the cellular level. The human genome is thought to contain approximately 1500 protein kinases to control these processes. These enzymes add phosphate groups to target proteins to modify their functions in a reversible manner with protein phosphatases removing the phosphate groups. This project is concerned with studying a metabolic stress sensing protein kinase called the AMP acti ....Protein kinases are important regulatory enzymes involved in the control of virtually all physiological processes at the cellular level. The human genome is thought to contain approximately 1500 protein kinases to control these processes. These enzymes add phosphate groups to target proteins to modify their functions in a reversible manner with protein phosphatases removing the phosphate groups. This project is concerned with studying a metabolic stress sensing protein kinase called the AMP activated protein kinase and its substrates. During periods of high energy demand such as vigorous exercise or nutrient stress induced by starvation or ischaemia the AMP activated protein kinase is responsible for shutting down energy requiring metabolic pathways and accelerating metabolism including glucose uptake and fatty acid metabolism to restore cellular energy levels. The AMP activated protein kinase regulates key enzymes in the control of cholesterol and lipid (fatty acid) synthesis as well as endothelial NO synthase, a key regulator of blood pressure and platelet activity. For these reasons it is potentially important in cardiovascular disease. The AMP activated protein kinase also appears responsible for exercise induced glucose uptake and it is known that exercise helps restore glucose control in age onset or type II diabetic patients. Since the AMP acitivated protein kinase accelerates fatty acid metabolism it may also have a role in obesity. While many factors are thought to be involved in cardiovascular disease, diabetes and obesity the AMP activated protein kinase is a key metabolic regulatory enzyme relevant to the most important diseases in Australia. Understanding the structure and function of the AMP activated protein kinase as well as the genes that encode this enzyme is an important goal.Read moreRead less