Impact Of Beta Adrenergic Antagonsim On Energy Metabolism And Body Composition
Funder
National Health and Medical Research Council
Funding Amount
$118,557.00
Summary
Beta-blockers are drugs commonly used to treat high blood pressure, anxiety, migraines and irregular heart rhythms. They work by blocking the action of chemical messengers called catecholamines which increase metabolic rate, fat utilisation and heart function. The aim is to determine whether ?-blockers impair metabolic function of the body which may lead to obesity and a loss of fitness. Judicious use of these medications and consideration of alternatives may lead to better health outcomes.
This project will test the proposal that rising follicle-stimulating hormone (FSH) levels in ageing females directly accelerate reproductive failure and bone loss , major public health issues due to delayed childbearing and our rising ageing population. We have developed a unique mouse model with elevated FSH levels that cause premature female infertility. We will now use this model to determine the direct effects of high FSH upon ovarian and uterine function, as well as bone loss with age.
Bone Fragility: The Neglected Role Of Cortical Porosity
Funder
National Health and Medical Research Council
Funding Amount
$620,381.00
Summary
Cortical (outer shell) or compact bone constitutes 80% of the skeleton. It is not solid as implied by its name but made of inter-connected canals resembling a network of roads. We recently discovered that most of the bone loss with age occurs from these canals, not from t rabecular bone as currently believed. This suggests to know why and how bone breaks requires the study of the morphology of these canals and how they change with age. This is what we propose to do. It has never been done.
Osteoporosis is a major health burden resulting from bone fractures in older men and women due to progressive loss of bone and weakening of the skeleton. Although there are currently therapies to reduce bone loss, no current treatment effectively reconstructs lost bone. In this project, which is designed to identify new genes that may in the future be targeted by drugs to reverse osteoporosis, we have identified specific sets of genes that appear to work together to increase bone formation. This ....Osteoporosis is a major health burden resulting from bone fractures in older men and women due to progressive loss of bone and weakening of the skeleton. Although there are currently therapies to reduce bone loss, no current treatment effectively reconstructs lost bone. In this project, which is designed to identify new genes that may in the future be targeted by drugs to reverse osteoporosis, we have identified specific sets of genes that appear to work together to increase bone formation. This proposal is aimed at characterising these genes and the ways in which they work to determine whether they may be good targets for new osteoporosis treatments. We will examine the patterns of these genes in bone. We will also use cell cultures in which bone forming cells develop and function, to determine when the genes are expressed and how they function. We will test the ability of the candidate genes to cause an increase in the amount of bone forming activity in these cell cultures. An increase in bone formation may be caused by an increase in the number bone-forming cells, an increase in the activity of the cells, a decrease in cell death, or a combination of these changes. Each possibility will be tested. This research is important because of the need for new osteoporosis therapies to repair weakened bones. The knowledge resulting from this proposal has the potential to provide an important contribution to skeletal health and thus aged health worldwide.Read moreRead less
Investigation Of COX-2 Regulation Of Bone Turnover And Mechanically Induced Bone Formation By Genetic Overexpression.
Funder
National Health and Medical Research Council
Funding Amount
$440,750.00
Summary
This project is important because it uses novel experimental models to advance our knowledge of prostaglandin biology in normal and pathological bone remodelling, and the response of the skeleton to increased physical activity. We expect that a genetic modification in mice to increase the normal production of key prostaglandin enzymes, cyclooxygenase-2 (COX-2), in bone cells will increase the number of cells that remove bone (osteoclasts), and increase bone loss and the rate of bone turnover whe ....This project is important because it uses novel experimental models to advance our knowledge of prostaglandin biology in normal and pathological bone remodelling, and the response of the skeleton to increased physical activity. We expect that a genetic modification in mice to increase the normal production of key prostaglandin enzymes, cyclooxygenase-2 (COX-2), in bone cells will increase the number of cells that remove bone (osteoclasts), and increase bone loss and the rate of bone turnover when compared to normal mice. We believe this will occur via the effect of prostaglandins on expression of genes that control osteoclast formation. This will be tested by examining the structure of the skeleton, and the expression of certain genes, in transgenic mice at different ages from 2-8 months. These effects may be exacerbated in conditions of increased bone turnover, such as postmenopausal bone loss. This will be tested by examining the bone structure and gene expression in adult mice following removal of their ovaries. Due to the role of COX-2 in adaptation of bone to mechanical loading, we also expect the load-bearing skeleton to be more sensitive to increased weight-bearing activity. We will investigate this hypothesis by applying mechanical loads to the tibiae of mice in a controlled manner and then analysing the bone structure. Knowledge of specific pathways by which bone formation can be stimulated is important for developing novel approaches to induction and augmentation of osteogenesis in skeletal diseases associated with ageing or disability, or for maintenance of new bone around implants. The discovery that COX-2 is a key enzyme in mechanotransduction and osteoclastogenesis in bone, and a pharmacological target for modulating inflammation, has considerable clinical significance. Exploiting this knowledge requires precise knowledge of the role of this enzyme in bone remodelling and adaptation and our experiments will contribute significantly to that knowledgeRead moreRead less
The Mechanisms Of The Anabolic Actions Of Androgens In Bone.
Funder
National Health and Medical Research Council
Funding Amount
$470,960.00
Summary
Androgens (male sex hormones) are one of the few agents that increase bone formation. Androgens act by binding to a specific protein, the androgen receptor (AR). To understand exactly how androgens increase bone formation, we will study mice in which the AR is inactivated only in bone forming cells at specific stages of their development. Understanding the way in which androgens act on bone to increase size and strength will be of great benefit in the design of new treatments for osteoporosis.
Osteoporosis is a major health burden resulting from bone fractures in older men and women due to progressive loss of bone and weakening of the skeleton. No current treatment effectively reverses this bone loss. Using genetic models in mice, we have identified a pathway, involving the nerve signal molecule NPY, that is capable of inducing large (200 - 300%) increases in bone very rapidly (within a few weeks), in the skeleton of adult mice. This proposal is aimed at characterising this new pathwa ....Osteoporosis is a major health burden resulting from bone fractures in older men and women due to progressive loss of bone and weakening of the skeleton. No current treatment effectively reverses this bone loss. Using genetic models in mice, we have identified a pathway, involving the nerve signal molecule NPY, that is capable of inducing large (200 - 300%) increases in bone very rapidly (within a few weeks), in the skeleton of adult mice. This proposal is aimed at characterising this new pathway to assess its potential to provide new treatments for human osteoporosis. This research is important because of the size, rapidity and inducibility of the effect. Moreover, since it originates in the brain, it represents a quite novel mechanism by which the skeleton is potentially maintained and repaired. The experiments contained in the initial sections of the proposal are designed to assess not only the ability of the NPY-pathway to protect against bone loss but also to examine the possibility of repair to a fragile skeleton. The bone loss models chosen for study represent postmenopausal and age-related osteoporosis, two prevalent and increasingly common conditions in the aging world population. The latter section of the proposal seeks to clarify the mechanism by which the increase in bone formation occurs within the bone. Understanding the working of this pathway will be vital in developing future treatment regimens. This proposal investigates a novel, powerful and rapid pathway for repairing weakened skeletons. The knowledge resulting from this proposal has the potential to provide an important contribution to skeletal health and thus aged health worldwide.Read moreRead less