Enhancing The Cardioprotective Effect Of Diadenosine Tetraphosphate: Designing Inhibitors Against Ap4A Hydrolase
Funder
National Health and Medical Research Council
Funding Amount
$442,500.00
Summary
Ischemia describes the condition where blood flow in the blood vessels of the heart is decreased or blocked, preventing delivery of oxygen and nutrients to the heart. Ischemic preconditioning is a phenomenon where short bursts of ischemia, followed by reperfusion, actually protect the heart from a subsequent longer period of ischemia. The biochemical signalling events involved in preconditioning are complex and incompletely defined, but most likely involve multiple pathways, although the mitocho ....Ischemia describes the condition where blood flow in the blood vessels of the heart is decreased or blocked, preventing delivery of oxygen and nutrients to the heart. Ischemic preconditioning is a phenomenon where short bursts of ischemia, followed by reperfusion, actually protect the heart from a subsequent longer period of ischemia. The biochemical signalling events involved in preconditioning are complex and incompletely defined, but most likely involve multiple pathways, although the mitochondrial ATP-dependent potassium channel may be in common with most pathways. Pretreatment with the compound diadenosine tetraphosphate (Ap4A) mimics ischemic preconditioning with noticeable reductions in tissue necrosis (cell death). This treatment has been shown in experimental work to protect the heart during periods of stress such as in heart surgery or recovery from an ischemic event. The biological site of action by Ap4A may be the mitochondria ATP-dependent potassium channel or an associated protein. Ap4A can be degraded by enzymes located inside and on the outside of heart cells, notably by two forms of Ap4A hydrolase. We will use antibody assays to understand the specific localization and amount of Ap4A hydrolase before and after ischemia and after ischemic preconditioning in human heart muscle and blood vessels. We propose to determine the structure of the enzyme and use novel computer methods to screen databases for potential inhibitors. These inhibitors of Ap4A hydrolase activity could aid the design of a potent inhibitor that would prevent Ap4A hydrolase from degrading Ap4A and therefore enhance the cardioprotective properties of Ap4A as well as minimizing side effects from the break down of Ap4A. We will also use these inhibitors and other known non-degradable Ap4A analogues in bioassays to test the relative significance of Ap4A hydrolase present in different cellular locations.Read moreRead less
Discovery And Mechanisms Of Host Cell Factors In HIV Uncoating
Funder
National Health and Medical Research Council
Funding Amount
$635,098.00
Summary
HIV entry into the host cell involves release of its capsid, a protein shell protecting the viral genome. The capsid hijacks host proteins to cloak itself from cellular defenses while the cell has evolved sensors that can block viral infection. This proposal aims to discover proteins involved in this arms race between host and virus and decipher how they control capsid disassembly. This insight will help design new drugs against HIV infection and new ways to deliver genes for gene therapies.
Antibiotic resistance is a looming public health crisis. New antibiotics with new mechanisms of action are desperately needed. The long-term goal of this research is to develop new drugs that disarm bacteria to overcome the problem of antibiotic resistance.
Plasmin is a complex enzyme that performs major roles in removal of blood clots, wound healing and in tumor metastasis. Here we will understand how plasmin function is regulated at the molecular level. These key insights will be of future use in the development of therapeutics targeting the plasmin system in cancer and clotting diseases.
Environmental metagenomics, metaproteomics and novel bioactives from microbial communities in Antarctic lakes. This program will derive an integrated understanding of microbial ecology which is essential for determining ways of preserving the health of the World's ecosystems. Through this, Australia will remain a world leader in Antarctic biology, strengthening Australia's reputation in technologically innovative scientific programs of global significance, training local scientists in cutting ed ....Environmental metagenomics, metaproteomics and novel bioactives from microbial communities in Antarctic lakes. This program will derive an integrated understanding of microbial ecology which is essential for determining ways of preserving the health of the World's ecosystems. Through this, Australia will remain a world leader in Antarctic biology, strengthening Australia's reputation in technologically innovative scientific programs of global significance, training local scientists in cutting edge genomic biology and fostering the interests of the international community in sciences ranging from microbial ecology to bioprospecting. Novel biodegradable enzymes will be developed to replace harsh chemicals providing environmentally friendly, cheaper and more effective agents for use in medical, biotechnological, industrial and biodefense applications.Read moreRead less
How does the chromatin remodeller CHD4 regulate gene expression? The mechanisms that determine how genes are switched on and off in different tissues and at different times are in many ways still mysterious. It is well established that gene expression patterns in complex organisms are determined in part by the manner in which DNA is physically packaged. Our aim is to define new aspects of these mechanisms that revolve around molecular motors that regulate DNA packaging. This foundational knowled ....How does the chromatin remodeller CHD4 regulate gene expression? The mechanisms that determine how genes are switched on and off in different tissues and at different times are in many ways still mysterious. It is well established that gene expression patterns in complex organisms are determined in part by the manner in which DNA is physically packaged. Our aim is to define new aspects of these mechanisms that revolve around molecular motors that regulate DNA packaging. This foundational knowledge will deepen our understanding of gene regulation in all complex organisms and will inform future efforts to rationally modulate gene expression patterns in agriculture, research and other important areas.Read moreRead less
Links between DNA replication and chromosome end maintenance. This project aims to increase knowledge of the way in which cells maintain their genomes, including the ends of their chromosomes, to enable their own survival. The ends of chromosomes (telomeres) are essential for survival and proliferation of the cells of most organisms. This project aims to determine the molecular details of a recently discovered link between telomere maintenance and the way cells maintain the integrity of their ge ....Links between DNA replication and chromosome end maintenance. This project aims to increase knowledge of the way in which cells maintain their genomes, including the ends of their chromosomes, to enable their own survival. The ends of chromosomes (telomeres) are essential for survival and proliferation of the cells of most organisms. This project aims to determine the molecular details of a recently discovered link between telomere maintenance and the way cells maintain the integrity of their genome. This is likely to lead to increased understanding of the fundamental biological process of genome maintenance, representing a significant scientific advance. The project expects to have far-reaching implications for biotechnology applications that require the survival of cells.Read moreRead less
New inhibitors of HIV based on cellular enzymes. Over 39 million people are infected with HIV worldwide. However, none of the most highly affected countries have yet reached the peak in AIDS-related illness and death, thus the global impact of HIV/AIDS will get significantly worse, before it gets better.
In Australia, HIV is again on the rise. Ironically, improved treatments that have extended life expectancy will cause the number of HIV infected Australians to rise for many years to come. ....New inhibitors of HIV based on cellular enzymes. Over 39 million people are infected with HIV worldwide. However, none of the most highly affected countries have yet reached the peak in AIDS-related illness and death, thus the global impact of HIV/AIDS will get significantly worse, before it gets better.
In Australia, HIV is again on the rise. Ironically, improved treatments that have extended life expectancy will cause the number of HIV infected Australians to rise for many years to come. Therefore many Australians will suffer from the combined impact of the AIDS illness itself, opportunistic infections, the side-effects of treatment and natural aging. We aim to develop new drugs to combat this disease to help people everywhere lead happier, healthier and more productive lives.Read moreRead less
Sensing atmosphere: Understanding the HNOX-protein gas-sensing capability and how it is affected by heme-oxidation. The project investigates how gas sensing heme-proteins from the novel HNOX (Heme-Nitric Oxide) family are able to discriminate between different gaseous ligands such as O2 and NO and how oxidation of the heme alters this response. The gas-sensing capability of the HNOX proteins is crucial for organisms ranging from bacteria to humans. Thus, understanding of these signalling mechani ....Sensing atmosphere: Understanding the HNOX-protein gas-sensing capability and how it is affected by heme-oxidation. The project investigates how gas sensing heme-proteins from the novel HNOX (Heme-Nitric Oxide) family are able to discriminate between different gaseous ligands such as O2 and NO and how oxidation of the heme alters this response. The gas-sensing capability of the HNOX proteins is crucial for organisms ranging from bacteria to humans. Thus, understanding of these signalling mechanisms will have a strong impact on many scientific fields from the control of pathogen growth to human blood pressure regulation. This collaboration will establish Australian scientists and as world-leading in the field of NO and redox signalling. This development will also be of substantial benefit for the training of the next generation of Australian students and scientists.Read moreRead less
Hierarchical Phosphorylation of Tyrosine Hydroxylase is Dependent on the Activation Sequence of Signaling Pathways. Protein phosphorylation is a fundamental process in biology. It controls protein expression and function in all cells. Hierarchical phosphorylation is defined as the phosphorylation of a protein at one site leading to an altered phosphorylation at another site on the same protein and an altered biological outcome. We have discovered that the enzyme tyrosine hydroxylase undergoes a ....Hierarchical Phosphorylation of Tyrosine Hydroxylase is Dependent on the Activation Sequence of Signaling Pathways. Protein phosphorylation is a fundamental process in biology. It controls protein expression and function in all cells. Hierarchical phosphorylation is defined as the phosphorylation of a protein at one site leading to an altered phosphorylation at another site on the same protein and an altered biological outcome. We have discovered that the enzyme tyrosine hydroxylase undergoes a form of hierarchical phosphorylation not previously reported. Here we examine hierarchical phosphorylation in rat and human tyrosine hydroxylase and its functional consequence in intact cells. The approaches and methods developed will also be applicable to investigation of hierarchical phosphorylation in other proteins.Read moreRead less