Furin: Carving-up Vital Substrates For Bone Remodelling And Homeostasis
Funder
National Health and Medical Research Council
Funding Amount
$815,972.00
Summary
Osteoporosis, or porous bone, is a disease characterized by low bone mass and structural deterioration of bone tissue, leading to bone fragility and an increased susceptibility to fractures. It is caused by an imbalance between the cells that are constantly reabsorbing and reforming bone. The proposed project will address furin as a novel regulator of bone remodelling.
The RgpA-Kgp Proteinase-adhesin Complex And Virulence Of Porphyromonas Gingivalis
Funder
National Health and Medical Research Council
Funding Amount
$527,310.00
Summary
Periodontitis is a bacterial-associated inflammatory disease of the supporting tissues of the teeth which can result in tooth loss. The disease is a major public health problem with a large economic burden. A bacterium Porphyromonas gingivalis has now been identified as a major causative agent of chronic periodontitis. We have identified a major virulence factor of P. gingivalis. This virulence factor is a complex of proteins, encoded by two genes, and is involved in binding and destruction of h ....Periodontitis is a bacterial-associated inflammatory disease of the supporting tissues of the teeth which can result in tooth loss. The disease is a major public health problem with a large economic burden. A bacterium Porphyromonas gingivalis has now been identified as a major causative agent of chronic periodontitis. We have identified a major virulence factor of P. gingivalis. This virulence factor is a complex of proteins, encoded by two genes, and is involved in binding and destruction of host tissue. When used as a vaccine in animal models the protein complex protects against P. gingivalis infection. Animal protective sera recognises a segment of the protein complex involved in binding to host substrates. The aim of this project is to continue this work on the characterisation of this complex and its role in virulence in an approach to ultimately develop a defined vaccine against P. gingivalis based on this protein complex, in particular the sequences involved in binding. The expected outcome of this research is the further biochemical characterisation of the RgpA-Kgp protein complex and its role in virulence as well as development of a defined vaccine prepared using recombinant DNA and chemical synthesis techniques that protects against P. gingivalis infection in animal models of disease.Read moreRead less
Experimental And Computational Study On Biomechanical Behavior Of Osteocytes
Funder
National Health and Medical Research Council
Funding Amount
$86,073.00
Summary
The experimental and computational methods (finite element method) are used to predict biomechanical behaviors of osteocytes under normal physiological loading, overloading or under-loading/disuse. This quantitative research will not only help to elucidate the mechanisms of mechanotransduction in osteocytes, it will provide important information that is also relevant to mechanobiology in general.
Molecular Mechanisms And Therapeutic Effects Of Novel Parthenolide Analogs On Osteolysis
Funder
National Health and Medical Research Council
Funding Amount
$562,815.00
Summary
Rheumatoid arthritis and osteoporosis are common bone diseases with features of bone loss. Drugs that inhibit bone loss are needed for the prevention and treatment of bone diseases. The proposed research explores the potential use of novel herbal inhibitors for the suppression of bone resorbing cells, and their potential as treatments for bone loss.
Polymicrobial Pathogenesis In A Murine Periodontitis Model.
Funder
National Health and Medical Research Council
Funding Amount
$235,500.00
Summary
Severe periodontal disease is a chronic inflammatory disease of the tooth's supporting tissues and is associated with specific pathogenic bacteria. The disease has a large economic burden and is a major public health problem. Three bacterial species have recently been shown to be closely associated with advanced periodontal disease in humans. One of these three bacterial species has been shown to produce periodontal disease in a mouse model of disease and the major proteins on the cell surface o ....Severe periodontal disease is a chronic inflammatory disease of the tooth's supporting tissues and is associated with specific pathogenic bacteria. The disease has a large economic burden and is a major public health problem. Three bacterial species have recently been shown to be closely associated with advanced periodontal disease in humans. One of these three bacterial species has been shown to produce periodontal disease in a mouse model of disease and the major proteins on the cell surface of this bacterium have been characterized. Further, in this mouse model it has been demonstrated that killed cells of the bacterium or the major surface proteins when used as a vaccine prevent development of disease. The purpose of the current proposal is to extend this work to include all three bacterial species that have been associated with disease in humans. The major surface proteins of all these bacterial species when grown together as high density polymicrobial complexes will be determined. Recent results have shown that in high-density, polymicrobial cultures bacteria communicate using signalling systems which can alter the expression of cell surface proteins associated with disease. The ability of the three bacterial species, when grown in polymicrobial culture, to cause periodontal disease in the mouse model will be determined. This will allow the determination of whether a single species and-or multispecies vaccine is capable of protecting against disease in this model. The significance of the work is that it will increase our understanding of the bacteria associated with periodontal disease and it may lead to the development of an effective vaccine to help prevent disease in humans.Read moreRead less
Iron/hemin Transport Systems Of Porphyromonas Gingivalis
Funder
National Health and Medical Research Council
Funding Amount
$392,036.00
Summary
Periodontitis is a bacterial-associated disease of the supporting structures of the teeth and can result in tooth loss. The disease is classified as a major public health problem with an enormous economic burden. A bacterium, Porphyromonas gingivalis, has now been implicated as a major causative agent of periodontitis in adults. To survive and grow within humans pathogenic bacteria must be able to acquire essential elements, including iron. The human host has developed a variety of mechanisms to ....Periodontitis is a bacterial-associated disease of the supporting structures of the teeth and can result in tooth loss. The disease is classified as a major public health problem with an enormous economic burden. A bacterium, Porphyromonas gingivalis, has now been implicated as a major causative agent of periodontitis in adults. To survive and grow within humans pathogenic bacteria must be able to acquire essential elements, including iron. The human host has developed a variety of mechanisms to restrict the amount of iron available as a means of limiting the growth of bacterial pathogens. In response to this iron limitation Porphyromonas gingivalis has developed novel ways of obtaining this essential element. We have identified a novel iron transport system that P. gingivalis uses to obtain iron from the human host. A component of this transport system, FetB is a surface protein antigen. The aims of this project are to: i. Determine the mechanism by which this novel iron transport system functions by genetic manipulation of the organism using molecular biology techniques. ii. Determine how important this transport system is for the pathogenicity of the bacterium. iii. Prepare the FetB protein using recombinant DNA technology. iv. Test the recombinant FetB protein and another iron transport protein (Tlr) in animal models to determine their efficacy as a vaccine for periodontitis. The expected outcomes of this research are:- i. the understanding of how P. gingivalis transports iron. ii. an understanding of the importance of iron transport systems to the pathogenicity of the bacterium. iii. a P. gingivalis vaccine with efficacy in animals based on an iron transport protein(s).Read moreRead less
Cell Surface Protein Antigens Of Porphyromonas Gingivalis
Funder
National Health and Medical Research Council
Funding Amount
$339,634.00
Summary
Periodontitis is a bacterial-associated disease of the supporting structures of the teeth and can result in tooth loss. The disease is classified as a major public health problem with an enormous economic burden. A bacterium Porphyromonas gingivalis has now been identified as a major causative agent of periodontitis in adults. We have developed methods to rapidly identify all the surface protein antigens of P. gingivalis using mass spectrometry and then using recombinant DNA technology to expres ....Periodontitis is a bacterial-associated disease of the supporting structures of the teeth and can result in tooth loss. The disease is classified as a major public health problem with an enormous economic burden. A bacterium Porphyromonas gingivalis has now been identified as a major causative agent of periodontitis in adults. We have developed methods to rapidly identify all the surface protein antigens of P. gingivalis using mass spectrometry and then using recombinant DNA technology to express these recombinant antigens for testing in animal models of disease. The aim of this project is: (i) to rapidly identify cell surface protein antigens of P. gingivalis using novel techniques. (ii) prepare these antigens using recombinant DNA technology. (iii) use patient and healthy subject sera as well as animal antisera to screen the recombinant antigens for suitable candidates for an immunodiagnostic product and-or vaccine. (iv) test the recombinant antigens in animal models of disease in an approach to identify a candidate antigen for a vaccine. The expected outcomes of this research are that (i) we will develop techniques that can be used to characterise the cell surface antigens of any pathogenic bacterium. (ii) we will determine the organisation and the structure of the cell surface proteins of P. gingivalis. (iii) we will identify an abundant, unique and immunogenic protein of the P. gingivalis surface that will be a suitable candidate antigen for the development of a sensitive and specific immunodiagnostic. (iv) we will identify a cell surface antigen that when used as a vaccine in animals prevents disease caused by P. gingivalis.Read moreRead less
Regulation Of Bone Resorption And Formation In Health And Disease
Funder
National Health and Medical Research Council
Funding Amount
$5,596,183.00
Summary
Bone is continually being formed and broken down, and these two processes are critical forthe maintenance of a normal skeleton. These processes are dependent upon communication between the bone building and degrading cells, and the hormones growth factors and cytokines that are present in the circulation or produced in bone. The tightly regulated processes of bone formation and degradation need to remain equal, and are essential for the achievement and maintenance of skeletal strength and form. ....Bone is continually being formed and broken down, and these two processes are critical forthe maintenance of a normal skeleton. These processes are dependent upon communication between the bone building and degrading cells, and the hormones growth factors and cytokines that are present in the circulation or produced in bone. The tightly regulated processes of bone formation and degradation need to remain equal, and are essential for the achievement and maintenance of skeletal strength and form. Osteoporosis results from an excess of bone breakdown over formation, and our Program aims to identify the factors that regulate these processes, and develop new therapies that can modify them. We will also determine what it is about bone cell properties that make some cancers, especially those of breast and prostate, particularly prone to spread to bone.Read moreRead less
Effect Of Prostaglandin E2 On The Periodontium And Alveolar Bone Formation
Funder
National Health and Medical Research Council
Funding Amount
$211,527.00
Summary
Dental disease affecting the supporting structures of teeth (the periodontium), is prevalent in our society. Periodontal disease results in destruction of bone around teeth, loosening of teeth, compromised chewing function, and tooth loss. Over the last twenty years reports into the effects of prostaglandin E2 (PGE2) on the skeleton have been divided and controversial. While historically PGE2 has been reported to promote bone resorption, more recently it has been demonstrated that when PGE is pl ....Dental disease affecting the supporting structures of teeth (the periodontium), is prevalent in our society. Periodontal disease results in destruction of bone around teeth, loosening of teeth, compromised chewing function, and tooth loss. Over the last twenty years reports into the effects of prostaglandin E2 (PGE2) on the skeleton have been divided and controversial. While historically PGE2 has been reported to promote bone resorption, more recently it has been demonstrated that when PGE is placed in contact with mandibular bone, adjacent to erupted teeth, new bone and cementum formation occurs. The ability of PGE2 to induce new bone formation indicates a potential use for PGE2 in the management of bone loss associated with periodontal diseases, and the formation of new bone around dental implants, and around teeth following orthodontic movement. Growth factors are active in healing and have valuable applications in augmenting wound repair. Osseous and dental tissues are rich in growth factors, and these factors are involved with the regulation of bone metabolism as well as tissue repair, thus the action of PGE2 on the periodontium is most likely regulated via these factors. Since regeneration of the periodontium is a fundamental goal of dentistry, any treatment which leads to predictable formation of new connective tissues and their long term stability would be a major clinical advance.Read moreRead less