Linkage Infrastructure, Equipment And Facilities - Grant ID: LE210100036
Funder
Australian Research Council
Funding Amount
$950,000.00
Summary
A customised triple-beam microscope for precise fabricating/characterising . This project aims to establish a customised triple-beam microscope to enable precise fabrication and polishing (using ion beams) and characterisation (using electron beam) of a wide range of advanced materials. It will provide solutions to prepare ultra-high quality and artefact-free specimens for transmission electron microscopy studies, and allow fabrication of unique nanostructures and nanostructured templates for hi ....A customised triple-beam microscope for precise fabricating/characterising . This project aims to establish a customised triple-beam microscope to enable precise fabrication and polishing (using ion beams) and characterisation (using electron beam) of a wide range of advanced materials. It will provide solutions to prepare ultra-high quality and artefact-free specimens for transmission electron microscopy studies, and allow fabrication of unique nanostructures and nanostructured templates for high-performance applications. The customised features of the proposed instrument are the first of its kind in Australia. The new knowledge developed through this project will significantly impact on scientific insights and practical applications of new materials related to physics, chemistry, biology, geology and engineering.Read moreRead less
Platelet Glycoprotein Proteolysis: Novel Mechanisms And Risk Factors
Funder
National Health and Medical Research Council
Funding Amount
$441,473.00
Summary
Platelets are the richest source of amyloid precursor protein (APP) in the body. Platelet ADAM10 regulates both the expression and function of the major platelet collagen receptor GPVI, and protective APP processing. Coagulation protein Factor X has a role in activation of ADAM10. This activation is disrupted in blood that has been treated with direct oral anticoagulant (DOAC) rivaroxaban. This grant will investigate the implications for people taking rivaroxaban on regulation of APP and GPVI.
The Role Of A Presenilin 2 Truncation (PS2V) In Alzheimer's Disease
Funder
National Health and Medical Research Council
Funding Amount
$552,741.00
Summary
The Presenilin and APP proteins are centrally important in inherited, early onset Alzheimer's disease. We have discovered that a shortened form of Presenilin protein, "PS2V", appears to increase specifically the rate at which the APP protein is cleaved to produce the "Amyloid beta" protein fragment that is found in Alzheimer's disease brains. This occurs when brain cells are under oxidative stress. Understanding this process will facilitate development of appropriate therapeutic strategies for t ....The Presenilin and APP proteins are centrally important in inherited, early onset Alzheimer's disease. We have discovered that a shortened form of Presenilin protein, "PS2V", appears to increase specifically the rate at which the APP protein is cleaved to produce the "Amyloid beta" protein fragment that is found in Alzheimer's disease brains. This occurs when brain cells are under oxidative stress. Understanding this process will facilitate development of appropriate therapeutic strategies for the disease.Read moreRead less
The Role Of Gonadotropins In Regulating The Production Of Alzheimer's Beta Amyloid
Funder
National Health and Medical Research Council
Funding Amount
$400,278.00
Summary
Currently, about 160,000 Australians suffer from dementia; of which 50-70% are Alzheimer's disease (AD) cases. AD is characterised clinically by memory and personality changes and pathologically by deposition of amyloid. Of particular importance in the disease pathogenesis, is a small molecule called beta amyloid, of which the overproduction is thought to be central to the development of AD. Changes in the levels of the reproductive hormones, particularly low levels of oestrogen during menopause ....Currently, about 160,000 Australians suffer from dementia; of which 50-70% are Alzheimer's disease (AD) cases. AD is characterised clinically by memory and personality changes and pathologically by deposition of amyloid. Of particular importance in the disease pathogenesis, is a small molecule called beta amyloid, of which the overproduction is thought to be central to the development of AD. Changes in the levels of the reproductive hormones, particularly low levels of oestrogen during menopause or testosterone during andropuase, has been associated with the increased risk of developing AD and in altering the levels of beta amyloid. Furthermore, menopause and andropause are also characterised by changes in other reproductive hormones such as the gonadotropins. High levels of the gonadotropins have also been associated with the increased risk of developing AD. Therefore it is important to identify how these changes modify the risk of developing AD. This study examines the role of the gonadotropins in regulating beta amyloid levels in cell culture and in an animal model for AD. Furthermore, this study will assess, in the animal model, the use of gonadotropin lowering agents to reduce levels of beta amyloid. The results from this study will provide important data on how reproductive hormones regulate beta amyloid. Further insight into these mechanisms will provide therapeutic or preventative strategies for AD.Read moreRead less
Structure and dynamics of a multiprotein-mRNA complex involved in the regulation of gene expression. RNA/protein interactions are now recognised as a major control point in the regulation of gene-expression. Proteins such as HuR and the poly(C)-binding proteins (PCBPs) act to stabilise and transport specific messenger (m)RNAs, and thus determine their translation levels. In contrast to such an important function, very little is known about these protein/mRNA interactions at an atomic level. The ....Structure and dynamics of a multiprotein-mRNA complex involved in the regulation of gene expression. RNA/protein interactions are now recognised as a major control point in the regulation of gene-expression. Proteins such as HuR and the poly(C)-binding proteins (PCBPs) act to stabilise and transport specific messenger (m)RNAs, and thus determine their translation levels. In contrast to such an important function, very little is known about these protein/mRNA interactions at an atomic level. The current study will investigate the structural and biophysical properties of a recently discovered HuR/PCBP/mRNA complex implicated in the regulation of androgen receptor expression. This information has the potential to assist in the development of drugs to reduce AR expression in prostate cancer.Read moreRead less
Developing Novel Molecules To Down-Regulate Src Family Tyrosine Kinases
Funder
National Health and Medical Research Council
Funding Amount
$201,261.00
Summary
Leukaemia and cancer cells have altered biochemical properties resulting in their high rate of growth compared to normal cells. One of the common biochemical characteristics of cancer-leukaemia cells is augmented activity levels of enzymes called tyrosine kinases. A major group of tyrosine kinase involved in several cancer-leukaemia types is called the Src family of tyrosine kinases. One member of this family called Lyn has been our focus of study for several years, investigating the signalling ....Leukaemia and cancer cells have altered biochemical properties resulting in their high rate of growth compared to normal cells. One of the common biochemical characteristics of cancer-leukaemia cells is augmented activity levels of enzymes called tyrosine kinases. A major group of tyrosine kinase involved in several cancer-leukaemia types is called the Src family of tyrosine kinases. One member of this family called Lyn has been our focus of study for several years, investigating the signalling pathways that it is involved in. This molecule has also been implicated in several specific leukaemia (Chronic Myeloid Leukaemia and Acute Myeloid Leukaemia) as well as cancer (Prostate, Colon, Breast) in recent years. We have identified a novel mechanism of down-regulation of this enzyme mediated by an adapter molecule called Cbp, which recruits the Lyn inactivating molecules Csk-Ctk as well as SOCS-1; together they inhibit the activity of Lyn and degrade the enzyme. Using our knowledge of the essential interaction elements of Cbp we will design and test various mini-Cbp molecules for their ability to inactivate and degrade Lyn in leukemic and cancer cells. These molecules may allow us to develop novel therapeutics capable of inactivating-degrading specific tyrosine kinases in cancer and leukaemia.Read moreRead less
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE150100148
Funder
Australian Research Council
Funding Amount
$150,916.00
Summary
An STM/AFM Facility for Electroactive Materials Characterisation. A Scanning Tunnelling Microscope (STM)/Atomic Force Microscope (AFM) facility for electroactive materials characterisation: This project is expected to address an identified need for the characterisation of electroactive structures using scanning probe microscopy and builds on local expertise in allied methods. The instrumentation includes an electrochemical STM for electrical testing of molecular wires, switches, transistors and ....An STM/AFM Facility for Electroactive Materials Characterisation. A Scanning Tunnelling Microscope (STM)/Atomic Force Microscope (AFM) facility for electroactive materials characterisation: This project is expected to address an identified need for the characterisation of electroactive structures using scanning probe microscopy and builds on local expertise in allied methods. The instrumentation includes an electrochemical STM for electrical testing of molecular wires, switches, transistors and other single molecule electronic components, together with a pico-force tunnelling AFM (PF-TUNA) for the measurement and correlation of nano mechanical and electrical properties of fragile structures over larger areas. The facility will be a core asset for researchers that use electroactive material on conducting substrates in fields including fundamental corrosion science, nanotechnology, and moltronics.Read moreRead less
Characterization Of Novel Regulators Of Erythropoiesis
Funder
National Health and Medical Research Council
Funding Amount
$437,545.00
Summary
Mature red and white blood cells develop from hemopoietic stem cells in the adult bone marrow. The production of red blood cells is primarily controlled by the hormone erythropoietin (epo). The availability of this hormone in a recombinant form has aided in the treatment of numerous forms of anaemia resulting from kidney failure, malignancies, and AIDS. Previously we had identified that the protein Lyn must be present inside primitive red blood cells for epo to stimulate them to become mature fu ....Mature red and white blood cells develop from hemopoietic stem cells in the adult bone marrow. The production of red blood cells is primarily controlled by the hormone erythropoietin (epo). The availability of this hormone in a recombinant form has aided in the treatment of numerous forms of anaemia resulting from kidney failure, malignancies, and AIDS. Previously we had identified that the protein Lyn must be present inside primitive red blood cells for epo to stimulate them to become mature functional cells. We have identified six molecules which interact with Lyn in red blood cells. We have shown that amolecule called HS1 is important for epo function in individual red blood cells and now we plan to investigate its functions in whole animals, including mice that lack the HS1 gene. We have also shown that a molecule called Trip1 is important for red blood cell development. Interestingly, this molecule also interacts with the thyroid hormone receptor and can influence the effects of epo and thyroid hormone on red blood cell development. The interplay between these two hormones will be looked at in more detail both at the cell and whole animal levels in normal mice and those lacking the thyroid hormone receptor gene. The third Lyn binding molecule we isolated is a novel gene-we have named it ankyrin repeat protein in line with the molecules it is related to. This gene is expressed in red blood cells and we aim to investigate what role it plays in the development of these cells. The fourth gene is also novel and is closely related to another called AFAP-110, which can exert effects on the structure of a cell. Its role in red blood cell structure will also be investigated. Finally, the last two molecule we have identified are both novel and are unrelated to any other known proteins. As above, the effects of these two molecules on red blood cell development will be investigated.Read moreRead less
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0560712
Funder
Australian Research Council
Funding Amount
$630,837.00
Summary
State-of-the-art biophysical tools for the characterisation of molecular interactions. In the current era of 'the genome' there is more demand than ever before for the characterisation of the gene products - the oligonucleotides and proteins that carry out the important functions in the cell. The current proposal is to acquire a suite of instrumentation to characterise the kinetics, thermodynamics and overall affinities of interactions between biological macromolecules and their physiological bi ....State-of-the-art biophysical tools for the characterisation of molecular interactions. In the current era of 'the genome' there is more demand than ever before for the characterisation of the gene products - the oligonucleotides and proteins that carry out the important functions in the cell. The current proposal is to acquire a suite of instrumentation to characterise the kinetics, thermodynamics and overall affinities of interactions between biological macromolecules and their physiological binding partners or with novel ligands. This will reveal the role of the macromolecules of interest in the cell, and potentially lead to the discovery of drug molecules which could interfere with molecular interactions underlying disease.Read moreRead less