Glycomic Control Of Cartilage Extra Cellular Matrix Turnover
Funder
National Health and Medical Research Council
Funding Amount
$706,289.00
Summary
Small, naturally occurring glycomic molecules control cartilage matrix turnover. We have synthesised small synthetic analogues of the naturally occurring molecules, and demonstrated their ability to regulate signalling pathways. This project will test and mathematical model the synthetic molecules in cell and tissue assays to define their properties and tissue effects, and assess their suitability as a drug delivery system. The results will be an important step towards designing new ways of trea ....Small, naturally occurring glycomic molecules control cartilage matrix turnover. We have synthesised small synthetic analogues of the naturally occurring molecules, and demonstrated their ability to regulate signalling pathways. This project will test and mathematical model the synthetic molecules in cell and tissue assays to define their properties and tissue effects, and assess their suitability as a drug delivery system. The results will be an important step towards designing new ways of treating osteoarthritis and other cartilage diseases.Read moreRead less
Proteomics Of Arthritis: Exploring Mechanisms Of Cartilage Degradation And Biomarker Identification
Funder
National Health and Medical Research Council
Funding Amount
$592,034.00
Summary
Arthritis is a major clinical and socio-economic problem. Arthritis involves the destruction of cartilage in joints. However, the mechanisms of initiation and progression of cartilage destruction remain poorly understood. Our studies will use new proteomic approaches to identify the changes in protein synthesis and degradation in mouse models of arthritis. This will provide critical information on disease mechanisms and for the development of diagnostic biomarkers and therapeutic approaches
Bone-specific Sclerostin And SIBLING Proteins In Osteoarthritis: Novel Contributions To Cartilage And Bone Pathology
Funder
National Health and Medical Research Council
Funding Amount
$441,058.00
Summary
Arthritis is a major clinical problem and involves the destruction of cartilage in joints. However, the mechanisms of how this cartilage destruction is initiated and progresses remain poorly understood. We recently discovered that that three proteins that play a role in bone are also produced in cartilage and are increased in cartilage during osteoarthritis. We will determine the role of each of these in the disease mechanism to provide new therapeutic and biomarker targets.
The Role Of A Novel Extracellular Matrix Protein, WARP, In Cartilage Development, Function And Pathology
Funder
National Health and Medical Research Council
Funding Amount
$482,500.00
Summary
The environment outside all cells is absolutely essential for normal growth and development. In order to undertand many disease and developmental processes it is critical that we acquire a detailed understanding of the various extracellular matrix components and how they interact to form a functional extracellular matrix. We recently discovered a new extracellular matrix protein which we have named WARP for von Willebrand factor A-domain-related protein. Our experiments demonstrate that WARP is ....The environment outside all cells is absolutely essential for normal growth and development. In order to undertand many disease and developmental processes it is critical that we acquire a detailed understanding of the various extracellular matrix components and how they interact to form a functional extracellular matrix. We recently discovered a new extracellular matrix protein which we have named WARP for von Willebrand factor A-domain-related protein. Our experiments demonstrate that WARP is an important constituent of the three-dimensional structure of the extracellular matrix of the articular surface of cartilage. We can show that WARP forms large-scale structures in tissue culture experiments and in extracts from mouse cartilage, and we have some new data which suggests that WARP interacts specifically with collagen II, a large and quantitatively major component of cartilage. We will explore the function of WARP in cartilage and include in vitro experiments that will reveal information about its distribution, tissue forms, and interactions with other extracellular matrix components (PART 1). To define the in vivo role of WARP we will generate a WARP gene knockout mouse (PART 2). These experiments will provide valuable information about the structure of the cartilage in the joint on the surface of bone and in particular the function of WARP in this structure. Since WARP is at the articular cartilage surface we asked whether WARP is lost in cartilage degeneration. In cartilage tissue grown in vitro under conditions that promote cartilage degradation, WARP is fragmented and released from the cartilage surface. We will explore this further in in vitro and in vivo models of cartilage breakdown (PART 3). Thus, in addition to promoting a new understanding of cartilage structure WARP has the exciting potential to become a specific biomarker for arthritis a major joint degenerative disease with high medical and financial cost to the community.Read moreRead less
Inherited Musculoskeletal Disorders: Molecular Genetics, Cellular Mechanisms And Therapies
Funder
National Health and Medical Research Council
Funding Amount
$621,458.00
Summary
My goal is to understand the causes of inherited muscular dystrophies and disorders affecting development of the skeleton. I study muscular dystrophies caused by collagen VI mutations, provide diagnosis for patients and families, and identify how and why the changes cause muscle disease. I am searching for genes that modify muscular dystrophy severity and exploring potential therapies. I discovered a new gene for inherited arthritis and am searching for genes for other skeletal disorders.
Modelling TRPV4 Skeletal Disorders Using Human IPSCs
Funder
National Health and Medical Research Council
Funding Amount
$1,171,187.00
Summary
Inherited skeletal disorders are a significant disease burden. Many gene mutations have been defined but we only have limited understanding about how they cause the disease. We will use patient skin cells and new in vitro re-programing technology to induce them to form cartilage cells to produce “disease in a dish” models of human skeletal disorders. These models will allow us to answer questions about how specific mutations cause disease and identify potential therapies
Cartilage Destruction In Arthritis: Mechanism Of Aggrecanase And Matrix Metalloproteinase Action In Vivo And In Vitro
Funder
National Health and Medical Research Council
Funding Amount
$703,180.00
Summary
Arthritis is a disease that causes pain, deformity and disability. The lack of adequate therapies for arthritis is partly a reflection of our limited understanding of the biochemical events involved in disease progression and cartilage destruction. Two distinct families of enzymes are present in cartilage. These are the MMP and the ADAMTS family. These enzyme families are important for cartilage turnover in normal growth and skeletal development. However unregulated enzyme activity resulting in ....Arthritis is a disease that causes pain, deformity and disability. The lack of adequate therapies for arthritis is partly a reflection of our limited understanding of the biochemical events involved in disease progression and cartilage destruction. Two distinct families of enzymes are present in cartilage. These are the MMP and the ADAMTS family. These enzyme families are important for cartilage turnover in normal growth and skeletal development. However unregulated enzyme activity resulting in accelerated cartilage breakdown leads to the pathology recognised as arthritis. While some activities of the MMP and ADAMTS families have been studied in the laboratory, there have been no in vivo studies to determine which family is responsible for cartilage destruction, and which is therefore most appropriate for targeting by drugs. This project will create genetically-modified mice, resistant to either the MMP or the ADAMTS enzymes. The mice will be used in experimental arthritis models to determine which enzymes play the major role in initiating disease, which enzymes are involved in disease progression and which enzymes may be important for repair. In parallel studies, the highly specialised matrix molecule, keratan sulphate, will be studied for its role in cartilage destruction. There is preliminary evidence to suggest that keratan sulphate may be involved in the regulation of ADAMTS activity. The possible direct and indirect modalities of keratan sulphate action will be investigated. The results of this arthritis project will (a) yield new information on the mechanism of disease action; (b) identify targets for the rational design of disease-modifying drugs; (c) elucidate biochemical processes involved in normal skeletal growth and cartilage repair; and (d) provide new in vivo models for testing the efficacy of arthritis therapies.Read moreRead less
Oxidation Of Arterial Extracellular Matrix By Myeloperoxidase-derived Oxidants
Funder
National Health and Medical Research Council
Funding Amount
$183,266.00
Summary
It is well established that changes occur in the composition and nature of the extracellular matrix present in the artery wall during the development of atherosclerosis. The changes that occur in this matrix affect both the mechanical and physical properties of the arterial wall (e.g. its ability to cope with the high pressures genrated by the pumping of blood from the heart) and the adhesion of cells. It is well established that certain key cell types do not adhere well, or grow properly, on al ....It is well established that changes occur in the composition and nature of the extracellular matrix present in the artery wall during the development of atherosclerosis. The changes that occur in this matrix affect both the mechanical and physical properties of the arterial wall (e.g. its ability to cope with the high pressures genrated by the pumping of blood from the heart) and the adhesion of cells. It is well established that certain key cell types do not adhere well, or grow properly, on altered or damaged matrix and this can result in either the loss of key cell types from the artery wall (e.g. loss of endothelial cells) and - or the proliferation and invasion of cells from other sources (e.g. smooth muscle cell invasion into the intimal space). There is circumstantial evidence that some of these changes occur via the formation of oxidants by the heme enzyme myeloperoxidase which is released from activated white cells. In this study we will employ recently developed analytical techniques to examine the nature of the alterations that are present in atherosclerotic plaques in comparison to normal human artery samples, and investigate the mechanisms by which such alterations arise. We will seek evidence for, or against, the involvement of myeloperoxidase-derived oxidants in the observed changes using specific markers which we have developed for the presence of such damage. This information will allow the rational design of strategies to interfere with the progression of atherosclerosis, which is the major killer of Australians.Read moreRead less
Novel Pathways Involving APC And PAR-2 In Cartilage Degradation In Osteoarthritis
Funder
National Health and Medical Research Council
Funding Amount
$448,834.00
Summary
Loss of the cartilage that normally lines the ends of bones is central to joint failure in arthritis and the need for replacement surgery. There are presently no treatments that stop cartilage breakdown in joint disease. This project investigates the role of a new pathway not previously thought to be active in cartilage, in the progressive damage seen in arthritis. Successful completion of these studies may provide a novel new strategy to treat joint disease.
Harnessing The Extracellular Matrix To Fight Obesity-induced Cognitive Impairment
Funder
National Health and Medical Research Council
Funding Amount
$645,205.00
Summary
The health burden of obesity in Australia is great, but the detrimental impact of obesity on brain function is not yet understood. This research program takes an innovative approach to define how obesity changes non-neuronal brain components that regulate neuroplasticity and protect neurons from damage. Outcomes will define new mechanisms to prevent obesity-induced cognitive impairment and critical knowledge gain leading to novel therapeutic approaches and policy changes to improve health.