Structural And Functional Studies On Glutamate Decarboxylase.
Funder
National Health and Medical Research Council
Funding Amount
$500,460.00
Summary
This proposal aims to determine the molecular structure of the two known isoforms of Glutamate Decarboxylase (GAD65 and GAD67). GAD in an essential human enzyme that is responsible for synthesising the primary inhibitory neurotransmitter gamma-aminobutyric acid (GABA). GABA functions in the human Central Nervous System (CNS) to dampen down excitatory signals. Proper control of GABA synthesis is important and perturbations in GABA levels lies behind human diseases such as intractable epilepsy, de ....This proposal aims to determine the molecular structure of the two known isoforms of Glutamate Decarboxylase (GAD65 and GAD67). GAD in an essential human enzyme that is responsible for synthesising the primary inhibitory neurotransmitter gamma-aminobutyric acid (GABA). GABA functions in the human Central Nervous System (CNS) to dampen down excitatory signals. Proper control of GABA synthesis is important and perturbations in GABA levels lies behind human diseases such as intractable epilepsy, depression and schizophrenia. As a result of this role, numerous common therapeutics (for example benzodiazepines) target proteins involved in the GABA neurotransmitter system. The goal of this proposal is to use the molecular structures of GAD to understand how to achieve fine control of GABA production. In addition to its role in the CNS, GAD is an important human autoantigen. Antibodies to one isoform of GAD, GAD65, are found in most patients with type I diabetes as well as certain patients with the movement disorder stiff person syndrome and related diseases of the CNS. It is suggested that the development of auto-antibodies may play a key role in the pathophysiology of these conditions. Despite sharing >80% sequence similarity with GAD65, autoantibodies to the other isoform of GAD, GAD67, are rarely found in patients with disease. The aim of this grant is to characterise the region of GAD that is targetted by autoantibodes. These data will allow us to understand why certain autoantibodes are able to inhibit GAD enzyme activity and why GAD65, but not GAD67 is recognised by autoantibodes.Read moreRead less
The Activation Of Lipoprotein Lipase By Apolipoprotein C-II
Funder
National Health and Medical Research Council
Funding Amount
$250,500.00
Summary
Abnormalities in blood lipid levels are common in our society. Treatment of these conditions adds a heavy burden to national health-care costs. Lipoprotein lipase is a plasma enzyme that plays a central role in maintaining safe blood lipid levels. The action of lipoprotein lipase in subjects on a western diet leads to the hydrolysis of about 150g of plasma triacylglycerol daily. Naturally occurring mutations in lipoprotein lipase, associated with a complete loss of enzyme activity, result in a h ....Abnormalities in blood lipid levels are common in our society. Treatment of these conditions adds a heavy burden to national health-care costs. Lipoprotein lipase is a plasma enzyme that plays a central role in maintaining safe blood lipid levels. The action of lipoprotein lipase in subjects on a western diet leads to the hydrolysis of about 150g of plasma triacylglycerol daily. Naturally occurring mutations in lipoprotein lipase, associated with a complete loss of enzyme activity, result in a high blood-lipids that can lead to premature atherosclerosis. Regulation of lipoprotein lipase occurs via an interaction with the regulatory protein apolipoprotein C-II. Individuals with apolipoprotein C-II deficiency also exhibit abnormal plasma lipid levels with an associated increased risk of coronary heart disease. These considerations demonstrate that the activation of lipoprotein lipase by apolipoprotein C-II is pivotal to the maintenance of normal blood lipid levels. The present proposal will establish the structure and orientation of apolipoprotein C-II in a lipid environment and provide a structural model for the activation of lipoprotein lipase by apolipoprotein C-II. These molecular details will serve as a model for the regulatory interactions of other apolipoproteins within lipoprotein particles and will generate leads for the development of new strategies for the treatment of blood lipid irregularities.Read moreRead less
Inhibiting pathological signalling in haematopoietic disease. Certain leukaemias and other blood diseases are caused by the mutation of one particular molecule, called Janus Kinase (JAK), inside our bodies. This project aims to understand the biochemical details of these diseases by studying this mutated molecule in detail. The project will aim to provide the information for developing effective therapeutics against these diseases.
This project aims to investigate novel ways to treat children with the inherited brain disorder known as MPS IIIA. This condition is currently untreatable and children generally die in their teens. We will use a mouse model of this condition to examine the effectiveness of combining two different treatment approaches, in order to maximise outcomes.
Chemical inhibition: a new approach to investigate the role of a key protease, CtHtrA, from Chlamydia trachomatis. Infertility in women frequently results from infection with Chlamydia trachomatis. This project will develop an inhibitor compound against a important protein from this bacteria. This will establish a new scientific approach to study Chlamydia trachomatis. This project will also contribute to the development of new treatments for infertility.
Biochemical Reconstitution Of The Ubiquitin Ligase Pathway Defective In Fanconi Anaemia
Funder
National Health and Medical Research Council
Funding Amount
$562,742.00
Summary
Fanconi Anemia (FA) is characterised by loss of vital blood cells but also 700x risk of developing leukaemia and other cancers. FA is caused by an inherited defect in one of 15 different genes that provide a signal and repair mechanism protecting cells from cancer causing mutations. By reconstructing this signaling mechanism in the test tube we will determine how it contributes to cancer protection, and highlight potential strategies for treatment of FA and leukaemia in the general population.
An Integrated Approach Towards Development of Highly Specific Chemotherapeutics. Many diseases are caused or can be treated by modifying the activities of particular enzymes. Molecules that affect enzymatic activities have potential as therapeutic agents. A successful approach to the discovery of new drug molecules is to design them based on very detailed knowledge of how the target enzyme works. In this project, a highly motivated team of scientists will use state of the art instruments and the ....An Integrated Approach Towards Development of Highly Specific Chemotherapeutics. Many diseases are caused or can be treated by modifying the activities of particular enzymes. Molecules that affect enzymatic activities have potential as therapeutic agents. A successful approach to the discovery of new drug molecules is to design them based on very detailed knowledge of how the target enzyme works. In this project, a highly motivated team of scientists will use state of the art instruments and their combined creativity to understand the intimate details of how one large group of enzymes work. The enzymes selected are the bimetallic hydrolases, many of which are associated with disorders including osteoporosis, mental illnesses, cystic fibrosis and various types of cancer.Read moreRead less
Guarding and evolving the genome: interactions between DNA-repair enzymes and damaged DNA. The application of structural biology techniques to the area of DNA repair allows us to understand the full implications linking genes and proteins to the molecular mechanisms of diseases such as cancer and hereditory conditions. Studies in this highly internationally competitive area are already established in the Bond laboratory, which has recently relocated to Australia. The use of forward-thinking stru ....Guarding and evolving the genome: interactions between DNA-repair enzymes and damaged DNA. The application of structural biology techniques to the area of DNA repair allows us to understand the full implications linking genes and proteins to the molecular mechanisms of diseases such as cancer and hereditory conditions. Studies in this highly internationally competitive area are already established in the Bond laboratory, which has recently relocated to Australia. The use of forward-thinking structural biology approaches to solve difficult technical problems will foster collaborations within Australia and with leading laboratories abroad, providing excellent up-to-date research training for students and postdoctoral researchers.
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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
Characterisation of the oxygen-sensing asparaginyl hydroxylase, FIH-1, and hydroxylase-specific antagonists. This research will provide fundamental information on how cells and whole organisms can sense and respond accordingly to oxygen deficiency. This information is fundamental for our understanding of embryo development and adult life in different environments, and central to the diagnosis and treatment of diseases such as stroke, cardiovascular disease, and cancer. This research will contrib ....Characterisation of the oxygen-sensing asparaginyl hydroxylase, FIH-1, and hydroxylase-specific antagonists. This research will provide fundamental information on how cells and whole organisms can sense and respond accordingly to oxygen deficiency. This information is fundamental for our understanding of embryo development and adult life in different environments, and central to the diagnosis and treatment of diseases such as stroke, cardiovascular disease, and cancer. This research will contribute to our basic knowledge of these processes, provide invaluable information about the specific genes and proteins involved, and provide direct information about the therapeutic potential of specific drugs or inhibitors designed to target this oxygen response in human disease.Read moreRead less