Osteocytes (OY) are the most abundant cell type in bone whose high density and viability are essential for healthy bone. We have found that vitamin K, vitamin D and strontium, promote human OY differentiation. We will test these in novel models of human OY differentiation and survival, and in animal models of bone loss associated with vitamin D deficiency, menopause and glucocorticoid treatment. Our work will lead to a better understanding of human OY and give a new approach to treat osteoporosi ....Osteocytes (OY) are the most abundant cell type in bone whose high density and viability are essential for healthy bone. We have found that vitamin K, vitamin D and strontium, promote human OY differentiation. We will test these in novel models of human OY differentiation and survival, and in animal models of bone loss associated with vitamin D deficiency, menopause and glucocorticoid treatment. Our work will lead to a better understanding of human OY and give a new approach to treat osteoporosis.Read moreRead less
The Role Of Proteases In Deafness; Generation Of A Knockout Mouse For Tmprss3 As A Model Of Autosomal Recessive Deafness
Funder
National Health and Medical Research Council
Funding Amount
$70,880.00
Summary
Age-related hearing loss is the most common type of human hearing impairment, affecting approximately half the population by the age of 80. The interaction of predisposing genetic factors with environmental factors is responsible for most age-related hearing loss. Genes underlying genetically inherited hearing impairment also affect susceptibility to age-related hearing loss. Approximately 1-1000 children are born deaf and ~50% of these cases have a genetic cause. Autosomal recessively-inherited ....Age-related hearing loss is the most common type of human hearing impairment, affecting approximately half the population by the age of 80. The interaction of predisposing genetic factors with environmental factors is responsible for most age-related hearing loss. Genes underlying genetically inherited hearing impairment also affect susceptibility to age-related hearing loss. Approximately 1-1000 children are born deaf and ~50% of these cases have a genetic cause. Autosomal recessively-inherited defects are responsible for most cases of genetic deafness (70%) and patients have no other medical problems, indicating that only the inner ear is affected. Genes previously identified for genetic forms of deafness can be broadly classified as either ion channels (e.g. connexins) or structural proteins (e.g. myosins and collagens). We recently identified a novel gene, a transmembrane serine protease, TMPRSS3, which is mutated both in familial and sporadic cases of deafness. Different classes of mutations may cause either deafness from birth or childhood onset deafness. Thus, reduced expression or abnormal function of TMPRSS3 may be involved in age-related hearing loss. This discovery was the first description of a protease involved in hearing loss and the first gene family involved in congenital deafness for which a ready hypothesis for involvement in age-related hearing loss can be made. We will generate and characterize a mouse model to investigate the role of TMPRSS3 in inner ear function and development. We will also isolate and characterize additional members of the transmembrane protease gene family to investigate further the role of proteases in both genetic and age-related hearing loss. This may lead to a greater understanding of the function of the auditory system and, eventually, to new therapeutic protocols.Read moreRead less
We will seek to address an important clinical problem in orthpaedics, namely the bone loss that commonly occurs around joint replacement prostheses. Termed peri-prosthetic osteolysis (PO), this bone loss can result in the loosening and ultimate failure and need for revision of the artificial joint components. PO is thought to be caused by the body's reaction to wear particles generated from the articulating surface of the prosthesis. However, it has not previously been possible to accurately exp ....We will seek to address an important clinical problem in orthpaedics, namely the bone loss that commonly occurs around joint replacement prostheses. Termed peri-prosthetic osteolysis (PO), this bone loss can result in the loosening and ultimate failure and need for revision of the artificial joint components. PO is thought to be caused by the body's reaction to wear particles generated from the articulating surface of the prosthesis. However, it has not previously been possible to accurately explore the relationship between prothesis wear and PO, or the progression of PO, because of a lack of techniques to image and measure the volume of PO around metal prosthesis components. We have developed a means to accurately and reproducibly measure the volume of bone loss, using CT, and will do so longitudinally in joint replacement patients to obtain the first information about the progression of PO. New computer based methods will be used concurrently to relate prosthesis wear and migration parameters to PO. Patients who come to surgery for replacement of failed prostheses will be investigated further by analysis of the tissues involved in the bone loss around prostheses. Basic science experiments will seek to understand the underlying causes of PO and the findings will be important in interpreting the clinical results. An animal model will be used to seek approaches to inhibiting the pathological response to wear particles. The significance of these studies is that they will lead to improved outcomes for joint replacement patients, increasing the interval to revision surgery, which is both extremely costly and brings an attendant morbidity and mortality.Read moreRead less
Hearing Protection Conferred By P2X2 Receptor Signaling In The Cochlea
Funder
National Health and Medical Research Council
Funding Amount
$580,019.00
Summary
Hearing loss from noise damage and ageing is the principal sensory disability in our society. This project will determine the contribution of the P2X2 receptor to protection from noise-induced hearing loss. We have found that P2X2 knockout mice have minimal temporary threshold shift. We will investigate the physiological basis for this and determine why this mouse model has greater hearing loss with intense sound and faster age-related hearing loss compared with wildtype controls.
The Role Of Mitochondrial DNA In Age-related Hearing Loss
Funder
National Health and Medical Research Council
Funding Amount
$260,475.00
Summary
Hearing loss is an extremely common and under-studied age-related disability, affecting 39% of Australians aged 50 years or older. Both genetic and environmental factors may contribute to the development of age-related hearing loss. Human genetic material (DNA) resides in two places in body cells; the nucleus and in organelles called mitochondria. This is due to the fact that mitochondria were derived from bacteria that were engulfed by the cell back in primordial life. Although this genetic mat ....Hearing loss is an extremely common and under-studied age-related disability, affecting 39% of Australians aged 50 years or older. Both genetic and environmental factors may contribute to the development of age-related hearing loss. Human genetic material (DNA) resides in two places in body cells; the nucleus and in organelles called mitochondria. This is due to the fact that mitochondria were derived from bacteria that were engulfed by the cell back in primordial life. Although this genetic material is different to nuclear DNA, it has an essential role in helping to provide energy for the cell. Genetic mutations in the DNA residing in the mitochondria have been associated with a number of conditions, usually affecting tissues that require large amounts of energy, such as the brain, muscle, heart, retina and the cochlea of the ear. The commonest clinical manifestation of mitochondrial disease is thought to be hearing loss. This project investigates the role that abnormal mitochondrial DNA plays in the development of hearing impairment by studying subjects from a representative Australian community who participated in a large population study of hearing loss. We will assess whether different sectors of mitochondrial DNA predispose particular individuals to the development of hearing loss or accelerate its onset. The Blue Mountains Hearing Study is able to take into account other factors known to be associated with hearing loss (industrial noise exposure, diabetes, smoking).Read moreRead less
The Impact Of Declining Tooth Loss On Oral Health Status And Dental Care Utilisation
Funder
National Health and Medical Research Council
Funding Amount
$144,375.00
Summary
Improved oral health has been well documented in Australia. Over recent decades the average number of decayed teeth among children has decreased. Among adults, the percentage with no natural teeth has also exhibited a decrease over time. While increased retention of natural teeth is an indicator of improved oral health status within the population, there may be some unexpected consequences of this success. Improved oral health has been associated with increased rather then decreased use of servi ....Improved oral health has been well documented in Australia. Over recent decades the average number of decayed teeth among children has decreased. Among adults, the percentage with no natural teeth has also exhibited a decrease over time. While increased retention of natural teeth is an indicator of improved oral health status within the population, there may be some unexpected consequences of this success. Improved oral health has been associated with increased rather then decreased use of services. Improvements in oral health manifested in the form of greater tooth retention, coupled with demographic trends towards growth in the population, may lead to an increased risk of oral disease with flow on effects on need and demand for care. Findings from one cross-sectional study in the USA have shown that people who retained higher numbers of teeth had more periodontal disease and dental caries experience, and reported a past pattern of visiting the dentist more frequently. The specific aims of this project are to examine the association of the number of natural teeth among middle-aged Australians with their oral health status, treatment needs and subsequent use of dental services. The outcome of this project will provide answers to two research questions. Firstly, it will see whether the retention of more teeth among adults is associated with higher levels of oral disease. Secondly, by following people over time it will be able to detect whether those who are retaining more teeth into adult age ranges have higher levels of use of dental services than their counterparts with fewer teeth. The answers to both of these research questions has significance for policy and planning in the area of dental public health by providing evidence as to the size and direction of expected future demand for and use of dental services in Australia.Read moreRead less
Osteoclasts (OC) are large multinucleated cells present in bone that are responsible for bone resorption. The renewal of bone and bone growth are regulated by the opposing actions of OCs and osteoblasts, cells that form new bone. Together, with other accessory cells in the bone marrow, these constitute 'bone-forming units' (BFU). Excess production or over-activation of OCs in the BFU leads to common bone conditions such as osteoporosis, Paget's disease and the bone lysis caused by bone cancers. ....Osteoclasts (OC) are large multinucleated cells present in bone that are responsible for bone resorption. The renewal of bone and bone growth are regulated by the opposing actions of OCs and osteoblasts, cells that form new bone. Together, with other accessory cells in the bone marrow, these constitute 'bone-forming units' (BFU). Excess production or over-activation of OCs in the BFU leads to common bone conditions such as osteoporosis, Paget's disease and the bone lysis caused by bone cancers. Osteoporosis causes a great deal of pain and disability and it alone costs the Australian taxpayers more than $400 million per year. OCs are formed from white blood cells that are present in the bone marrow and the blood. The recent discovery of a family of new factors that control the formation of OCs has enabled the generation of human OCs in the laboratory so now we can investigate the genes that control the process of conversion of white blood cells to OCs. An important advance in this project involves the use of cord blood that contains stem cells. These very na ve cells will enable us to study the very earliest genes that control differentiation of precursors to OC. We have found a number of genes that are regulated by these new bone-forming factors. In white blood cells the activation of particular genes can regulate OC formation. One example is vitamin D-upregulated gene, VDUP. This gene is of particular interest as it causes inhibition of the mechanism that leads to OC formation in the bone. Obviously, the ability to control a 'switch' that regulates OC formation may enable us to control the progress of bone loss in diseases such as osteoporosis. In this project, we intend to investigate how and why the genes that lead to OC formation are regulated and what influence the various bone cell factors have on the formation of bone-resorbing OCs. These studies will lead to the development of treatments for osteoporosis and other bone diseases.Read moreRead less