Development Of BRET Detection Systems: Tools For Functional Proteomics And Drug Discovery
Funder
National Health and Medical Research Council
Funding Amount
$376,320.00
Summary
The internal structure of articular cartilage is critical to its biomechanical function. Cartilage is one of the most intricate and difficult tissues to examine in-vivo. Maintenance of its functional characteristics depends heavily of the internal microstructure of the tissue, while conventional arthroscopy can only give a view of the surface and provides no information on the internal structure. Biopsy examination can also destroy the integrity of the tissue, making it impossible to concurrentl ....The internal structure of articular cartilage is critical to its biomechanical function. Cartilage is one of the most intricate and difficult tissues to examine in-vivo. Maintenance of its functional characteristics depends heavily of the internal microstructure of the tissue, while conventional arthroscopy can only give a view of the surface and provides no information on the internal structure. Biopsy examination can also destroy the integrity of the tissue, making it impossible to concurrently examine the structure and function of the tissue. The structure-function relationship is thus critical to the study and the advancement of clinical treatment techniques for cartilage disorders. Osteoarthritis is characterized by severe disruption to the cartilage matrix. The emergence of autologous chondrocyte implant (ACI) therapy as a method for repairing cartilage defects has further increased interest in clinical techniques for the examination of cartilage structure and function. The development of confocal microscopy facilitates internal examination of loaded tissue for the first time, enabling direct examination of the association between structure and function of the tissue. A prototype confocal arthroscope has been developed to facilitate clinical examination of cartilage structure. This, in turn, allows the functional characteristics of the tissue to be deduced. Cartilage exhibits little intrinsic repair making biopsies undesirable. Thus, with respect to cartilage in particular, the developed technologies promise to enable examination to a level of detail which was previously impossible. The current prototype arthroscope has demonstrated the feasibility of a genuine clinical instrument. This grant application seeks funds to conduct initial clinical trials in order to gain sufficient practical feedback to enable design and construction of a clinically ready system.Read moreRead less
Development Of Resonance Energy Transfer Technologies To Detect GPCR Heterodimer Complexes In Living Cells
Funder
National Health and Medical Research Council
Funding Amount
$205,555.00
Summary
G-protein coupled receptors are proteins at the surface of most cells in the body. They bind to drugs, transmitting signals into cells that change what cells are doing. Recent research indicates that different types of these proteins can interact with each other and when one of these protein combinations binds a drug, it acts differently to when the proteins act separately. The aim of our project is to find out which protein combinations exist and to find drugs that bind to them specifically.
Functional studies on a novel, brain-specific, Golgi ATP-binding protein in membrane trafficking. In cells specialised for communication such as neurones, protein transport constitutes a large part of total cellular activity. A primary pathway in protein transport is trafficking from the Golgi apparatus to the cell membrane; materials destined for the cell membrane and secretion are sorted, packed and transported from the Golgi apparatus. However, the mechanisms underlying these processes at the ....Functional studies on a novel, brain-specific, Golgi ATP-binding protein in membrane trafficking. In cells specialised for communication such as neurones, protein transport constitutes a large part of total cellular activity. A primary pathway in protein transport is trafficking from the Golgi apparatus to the cell membrane; materials destined for the cell membrane and secretion are sorted, packed and transported from the Golgi apparatus. However, the mechanisms underlying these processes at the Golgi remain largely unknown. We have recently cloned a novel ATP-binding protein specifically expressed at the Golgi apparatus in human brain, and hypothesise that this protein regulates Golgi protein trafficking by interacting with two other molecules, dynamin and calcium, during cell secretion.Read moreRead less
Role of 3'-phosphorylated phosphoinositides in neurosecretion. Neurons communicate through the release of neurotransmitter by synaptic vesicles. Minute changes underlie normal processes such as memory and modifications of neurotransmitter level contribute to a number of neurological diseases. I am interested in deciphering the role of phosphoinositides, an inner membrane-based lipid, during steps leading to the fusion of a synaptic vesicle with the plasma membrane. I have recently discovered tha ....Role of 3'-phosphorylated phosphoinositides in neurosecretion. Neurons communicate through the release of neurotransmitter by synaptic vesicles. Minute changes underlie normal processes such as memory and modifications of neurotransmitter level contribute to a number of neurological diseases. I am interested in deciphering the role of phosphoinositides, an inner membrane-based lipid, during steps leading to the fusion of a synaptic vesicle with the plasma membrane. I have recently discovered that phosphatidylinositol-3 phosphate production was critical for the vesicle to acquire the competence to fuse with the plasma membrane. This project aim to understand by which mechanism this lipid interacts with the release machinery to promote such priming step.Read moreRead less
The regulated movement of membrane receptors and ligands between the cell surface and intracellular compartments is vital to many cellular operations, including communication between cells and their environment. However, the molecular details of these sorting events remain poorly defined. Determination of the mechanisms that control the cellular distribution of receptors is critical for understanding normal cellular processes and in pathological processes like tumorigenesis.
Non-classical steroid signalling through SF-1 responsive genes: a key mechanism in environmental endocrine disruption, cancer, and aging. Endocrine disruption by pervasive manmade chemicals, which mimic natural hormones, and are found in plastics, cosmetics, and fire retardants, is known to cause developmental defects in model organisms and wildlife, with substantial risk also to human health. This risk increases with increasing population density and dependence on water recycling. Current tests ....Non-classical steroid signalling through SF-1 responsive genes: a key mechanism in environmental endocrine disruption, cancer, and aging. Endocrine disruption by pervasive manmade chemicals, which mimic natural hormones, and are found in plastics, cosmetics, and fire retardants, is known to cause developmental defects in model organisms and wildlife, with substantial risk also to human health. This risk increases with increasing population density and dependence on water recycling. Current tests to assess such substances use oversimplified modes of hormone action and grossly underestimate the risk of endocrine disruption. This proposal will yield new knowledge about how such substances act in the body, or on wildlife, and form the basis for new more sensitive methods of environmental monitoring.Read moreRead less
Investigation of the biochemical and physiological functions of the negative regulator of cytokine signalling SOCS-2. Cytokines exert their effects by binding and signalling through specific cell surface receptors to elicit their biological action, and if left unchecked, this signalling can cause significant tissue damage and toxicity. Our aim is to characterise a novel regulator of cytokine signalling, SOCS-2. SOCS-2 is strongly implicated in the regulation of post-natal growth as SOCS-2 defici ....Investigation of the biochemical and physiological functions of the negative regulator of cytokine signalling SOCS-2. Cytokines exert their effects by binding and signalling through specific cell surface receptors to elicit their biological action, and if left unchecked, this signalling can cause significant tissue damage and toxicity. Our aim is to characterise a novel regulator of cytokine signalling, SOCS-2. SOCS-2 is strongly implicated in the regulation of post-natal growth as SOCS-2 deficient animals are 40 percent larger than normal. Consequently, we wish to determine how SOCS-2 acts to limit the size of an animal and whether this involves regulation of growth hormone action.Read moreRead less
Activation mechanisms of store-operated calcium channels in liver cells. Currently, one of the most active areas of research in biology involves the molecular mechanisms that control the activity of cells. Defining these will provide a deeper understanding of normal function and disease, and provide potential therapeutic targets. This group has an international reputation for its work and it makes a major input to maintaining Australia as a significant contributor to this field. While its resea ....Activation mechanisms of store-operated calcium channels in liver cells. Currently, one of the most active areas of research in biology involves the molecular mechanisms that control the activity of cells. Defining these will provide a deeper understanding of normal function and disease, and provide potential therapeutic targets. This group has an international reputation for its work and it makes a major input to maintaining Australia as a significant contributor to this field. While its research has broad application in biology, its specific focus, calcium signalling in the liver, will provide the basis for understanding liver function and disease and, potentially, for developing new treatments for liver disease associated with abnormal calcium homeostasis.Read moreRead less
Characterisation of the novel mitochondrial protein (CABC1/ADCK3) and its role in protecting against oxidative stress. This is the first detailed characterisation and mechanistic study on a protein that protects against oxidative stress and neurodegeneration. Demonstrating the basis for this oxidative stress and its possible contribution to the cellular phenotype will be of benefit in understanding the disease process and ultimately designing approaches to minimise oxidative stress. An investiga ....Characterisation of the novel mitochondrial protein (CABC1/ADCK3) and its role in protecting against oxidative stress. This is the first detailed characterisation and mechanistic study on a protein that protects against oxidative stress and neurodegeneration. Demonstrating the basis for this oxidative stress and its possible contribution to the cellular phenotype will be of benefit in understanding the disease process and ultimately designing approaches to minimise oxidative stress. An investigation of this protein presents an opportunity for the investigator to work at the forefront in this field adding to Australia's scientific leadership in the area. It also represents an ideal project for post-graduate training and is a collaboration between groups in Brisbane and Melbourne. Read moreRead less