Interrelationships Between The Disc And Bone Of Lumbar Spinal Segments
Funder
National Health and Medical Research Council
Funding Amount
$423,625.00
Summary
The cause of back pain due to osteoarthritis, osteoporotic vertebral crush fracture, and ageing is poorly understood. Vertebral deformity, intervertebral disc disorganisation, and change to vertebral bone structure are features associated with degeneration of the spine and with back pain. Degenerative disc disease is one of the major causes of back symptoms and is believed to be associated with degeneration of the spine. Spinal degeneration includes disc degeneration, facet joint osteoarthritis, ....The cause of back pain due to osteoarthritis, osteoporotic vertebral crush fracture, and ageing is poorly understood. Vertebral deformity, intervertebral disc disorganisation, and change to vertebral bone structure are features associated with degeneration of the spine and with back pain. Degenerative disc disease is one of the major causes of back symptoms and is believed to be associated with degeneration of the spine. Spinal degeneration includes disc degeneration, facet joint osteoarthritis, compromised vertebral body bone quality, muscle and ligament alterations. It is assumed that these changes result in increased or abnormal spine motion and modified load distribution across the spinal joint. It has been found that with age, there is increased disorganisation of the intervertebral disc and decreased quality of vertebral cancellous bone. However, bones with the same density within the range of normal subjects, can show selective loss of bone structure and reduced load-bearing capacities of these vertebrae. An important concept here is that even for a given bone mass, fracture risk increases with age, supporting the view that there is a component of bone fragility that is independent of mass. Increased bone fragility may be associated with compromised cancellous bone structure. While the relationship between disc degeneration and changes in vertebral bone is commonly invoked, the mechanisms of this relationship have largely been overlooked, with age changes given more attention. However, it may be that intervertebral disc disorganisation modulates age-related bone changes within the spine. Disc degeneration may influence trabecular bone responses before changes with age put the patient at risk of vertebral crush fracture. We propose that the mature disc cannot effectively regenerate after damage, and thus responses to disc damage will be more readily observed in vertebral bone architecture than in the disc.Read moreRead less
Molecular Determinants Of Bone Remodelling In The Bone Microenvironment
Funder
National Health and Medical Research Council
Funding Amount
$317,640.00
Summary
There is little information regarding the expression of specific molecules in human bone tissue or their role in skeletal disease. The process of bone remodelling is fundamental for the maintenance of skeletal integrity. Our understanding of the molecular signalling involved in activating bone remodelling is principally derived from tissue culture and animal experiments. We will study human cancellous bone samples donated by patients undergoing surgery, and with the consent of the next-of-kin, t ....There is little information regarding the expression of specific molecules in human bone tissue or their role in skeletal disease. The process of bone remodelling is fundamental for the maintenance of skeletal integrity. Our understanding of the molecular signalling involved in activating bone remodelling is principally derived from tissue culture and animal experiments. We will study human cancellous bone samples donated by patients undergoing surgery, and with the consent of the next-of-kin, taken at autopsy. These molecular and histomorphometric studies will determine whether the understanding derived from tissue culture and animal experiments is consistent with associations demonstrable in the human cancellous bone microenvironment. The elucidation of the molecular signalling in the human bone microenvironment is essential for the effective diagnosis and treatment of bone disease. Recently reported studies have shown very persuasively that fatigue microdamage accumulates in the skeleton and is targeted for repair by remodelling. Our preliminary data shows that microcrack length is positively correlated with IL-11 mRNA gene expression. We will further investigate mRNA gene expression of a number of cytokines involved in bone cell signalling and their association with the level of microdamage in the bone. Using a animal model of controlled bone microdamage induction we will seek to determine the bone remodelling causal relationship between microdamage and cytokine signalling. Furthermore, the cellular and molecular mechanisms that lead to trabecular structures are not well understood. These studies will provide new insight into the processes that determine trabecular structures. This project will investigate these mechanisms and increase our understanding of bone cell function, essential for diagnosis and design of rational treatment for bone diseases.Read moreRead less
Intrinsic Bone Qualities In Fragility Fracture Patients: Mass, Microarchitecture, Mineralization And Damage Accumulation
Funder
National Health and Medical Research Council
Funding Amount
$447,027.00
Summary
Osteoporosis drug therapies have been associated with a significant reduction in fragility fracture. Patients receiving osteoporosis drugs, which have different effects on BMD, may have similar reductions in fractures. Furthermore, patients with fragility fractures may have abnormalities in bone structural and material properties. Changes to the process of bone renewal, due to drug therapy, may explain why fracture risk decreases where no detectable change to the structure of bone has been detec ....Osteoporosis drug therapies have been associated with a significant reduction in fragility fracture. Patients receiving osteoporosis drugs, which have different effects on BMD, may have similar reductions in fractures. Furthermore, patients with fragility fractures may have abnormalities in bone structural and material properties. Changes to the process of bone renewal, due to drug therapy, may explain why fracture risk decreases where no detectable change to the structure of bone has been detected. It has also been shown that when bone renewal is suppressed microdamage accumulates in bone tissue, leading to reduced bone toughness. The toughness of bone is of primary importance in relation to fragility fractures, and it has been shown that the fatigue strength and fracture toughness (work to fracture) reduce considerably with age. This proposed study would seek to elucidate the role of bone tissue-level properties in determining bone quality for human subjects: patients with fragility hip fractures on no osteoporosis drugs therapy, hip fracture patients on osteoporosis drugs therapies, and normal age- and sex-matched individuals. Our laboratory has extensive experience in the analysis of the structure of human bone tissue. Recently, we have developed novel and unique techniques to assess bone quality, using micro-CT, backscatter SEM imaging, confocal microscopy and immunohistochemistry. This multifaceted study will identify at the bone tissue-level the structural mechanisms (micro-architecture, mineralisation, and microscopic cracking) that are indicative of the efficacy of fragility fracture drugs. Better understanding of the mechanisms by which bones are less likely to fracture will enable better targeting of osteoporosis drug therapy to individuals at risk of fragility fracture.Read moreRead less
A Prospective Study Of The Psychiatric & Medical Characteristics Of Post-infective Fatigue & Chronic Fatigue Syndrome.
Funder
National Health and Medical Research Council
Funding Amount
$500,000.00
Summary
This project forms the central component of a larger set of studies which investigate competing psychiatric, immunological and infective models of the causes of a number of chronic fatigue syndromes, including post-infective fatigue. The study takes place in western NSW where certain viral illnesses (Glandular Fever, Ross River Virus) and a non-viral infection (QF) are common and have been associated with prolonged fatigue states. The study follows patients from laboratory-documented infections ....This project forms the central component of a larger set of studies which investigate competing psychiatric, immunological and infective models of the causes of a number of chronic fatigue syndromes, including post-infective fatigue. The study takes place in western NSW where certain viral illnesses (Glandular Fever, Ross River Virus) and a non-viral infection (QF) are common and have been associated with prolonged fatigue states. The study follows patients from laboratory-documented infections with appropriate infective, immunological and psychological measures throughout the course of their acute illness, the early recovery period and for the next 12 months. These patients are compared with people who present to their doctor with other forms of medically-unexplained fatigue. Very few previous studies have used an appropriate prospective design and followed patients with documented illness from the onset through to the development of specific forms of chronic fatigue. Further, the study is unique in terms of the range of viral and non-viral agents being investigated. It relies on the combined psychiatric, immunological and infective disease expertise of a group of researchers with an international reputation for the successful completion of such multidisciplinary projects. The initial phase of the study has demonstrated that the research team has the capacity to complete this project. Initial results have already demonstrated the potential roles of psychological and immunological factors in causing some cases of prolonged fatigue. Further, the initial results indicate that two key symptom sets (fatigue, psychological distress) can be adequately measured during the recovery phase and are predicted by differing psychological factors. The study will result in the identification of different psychiatric risk factors to chronic fatigue, assist development of clear diagnostic guidelines for post-infective fatigue and guide relevant aetiological and treatment research.Read moreRead less
Energy Use And Work Output By Cross-bridges In Fast- And Slow-twitch Muscles
Funder
National Health and Medical Research Council
Funding Amount
$191,177.00
Summary
All voluntary movement is produced by the action of skeletal muscles. The muscles provide the mechanical power required to move the limbs and the body. To do so, they require energy which is ultimately derived from the breakdown of food. Therefore, we can describe the fundamental process underlying muscular contraction as the conversion of energy from a chemical form into a mechanical form. This project investigates the relationship between the breakdown of molecules that provide energy and the ....All voluntary movement is produced by the action of skeletal muscles. The muscles provide the mechanical power required to move the limbs and the body. To do so, they require energy which is ultimately derived from the breakdown of food. Therefore, we can describe the fundamental process underlying muscular contraction as the conversion of energy from a chemical form into a mechanical form. This project investigates the relationship between the breakdown of molecules that provide energy and the production of mechanical energy or work. Normal contraction involves many cyclic interactions between two proteins, actin and myosin. Each cycle produces a tiny force that contributes to the shortening of the muscle. For over 30 years, it has been thought that energy required for each force producing cycle was provided by the breakdown of one energy-providing molecule, called ATP. Almost all current models of muscle contraction are based on this idea. Recently, data from studies using isolated actin and myosin and observing their interaction in vitro have indicated that many force-producing cycles may be performed with the energy from just one ATP. If this is correct, it will revolutionise our ideas about the way muscles convert chemical energy into mechanical energy. However, the interaction of proteins in a dish is far removed from a normal muscle and the aim of this project is to determine the relationship between force producing cycles and energy use in intact muscles. If multiple force-producing cycles can be powered by one ATP molecule in intact muscle too, then the current idea that the biochemical processes that release energy from ATP are intimately linked to the mechanical changes in myosin that occur as it produces force will be untenable. In short, we will have to rediscover how muscles convert chemical energy into mechanical energy and find out how that energy can be stored from one force-producing cycle to the next.Read moreRead less
The Relationship Between Fatigue, Sleepiness And Crash Risk While Driving
Funder
National Health and Medical Research Council
Funding Amount
$444,070.00
Summary
Driver fatigue is a major road safety problem that is currently managed by encouraging drivers to take breaks when they feel tired. Unfortunately we dont know whether drivers really are able to detect when they are too tired to drive safely or, if they can make this judgement, whether and what motivates them to stop driving. This research will look at driver awareness of fatigue effects and what indicators and motivators can be used to encourage them to respond to signs of impaired driving.
Muscle fatigue is common after exercise in healthy people. In many tasks, some muscles become more fatigued than others. Thus, the nervous system must often coordinate fatigued muscles (which produce less force) with unfatigued muscles. We will investigate how fatigue of one muscle alters the way the brain controls other muscles that are engaged in the same task or in unrelated tasks. This will aid understanding of the failures of coordination that lead to poor performance and injury.
CBS Domain Modulation Of Muscle Chloride Channels; Molecular Mechanism And Physiological Role.
Funder
National Health and Medical Research Council
Funding Amount
$523,455.00
Summary
Muscle chloride channels regulate how readily muscles are activated, particularly during muscle fatigue. Recently we have identified a feed-back mechanism linking chloride channel function to muscle acidosis and energy depletion, key factors in fatigue. Here we will investigate the molecular details of this mechanism and its role in muscle physiology and fatigue. This mechanism may present a future target for the treatment of myotonia, a condition where muscles are too readily activated.
How Changes In The Motor Cortex And Spinal Cord With Exercise Contribute To Fatigue In Humans
Funder
National Health and Medical Research Council
Funding Amount
$311,250.00
Summary
Fatigue with exercise is a common experience in healthy people and can be a problem in many illnesses. With fatigue people are less able to produce force with their muscles. Much of this weakness occurs because of events in the muscles but some results from changes in the nervous system. The size of the contribution of the nervous system to fatigue is not known for the kinds of exercise that cause fatigue in everyday life e.g. prolonged weak contractions like holding the shopping or a plate of f ....Fatigue with exercise is a common experience in healthy people and can be a problem in many illnesses. With fatigue people are less able to produce force with their muscles. Much of this weakness occurs because of events in the muscles but some results from changes in the nervous system. The size of the contribution of the nervous system to fatigue is not known for the kinds of exercise that cause fatigue in everyday life e.g. prolonged weak contractions like holding the shopping or a plate of food, rhythmic contractions like walking or painting a wall, and more vigorous exercise that causes changes in breathing and body temperature. The behaviour of nerve cells in the brain and spinal cord is altered in fatigue but how and why many of these changes occur, and how they affect the control of movements, is poorly understood. Three approaches are planned. In the first set of studies, we will use brain and nerve stimulation to measure the impact of sustained low-level activities on people's ability to drive their muscles fully. We will identify whether such activities, as well as increased demands on other body systems, can cause fatigue in the nervous system. In the second set of studies, we will investigate whether changes in the motor areas of the brain can alter peoples' performance of fatiguing motor tasks or their perception of how much effort the tasks take. Finally, we will use stimulation of the spinal cord to work out why motor nerve cells in the spinal cord fire more slowly with fatigue. Fatigue is an important symptom which is not confined to diseases of any one system in the body. For example, it is a major complaint in multiple sclerosis, cardiac failure, chronic obstructive airway disease, depression and cancer, as well as after chemotherapy, surgery, and viral illness. The implications of better understanding of the contribution of the nervous system to fatigue range from targeting treatments in patients to improving the performance of athletes.Read moreRead less
Role Of Nitric Oxide And Reactive Oxygen Species In Excitation-contraction Coupling In Skeletal Muscle.
Funder
National Health and Medical Research Council
Funding Amount
$163,250.00
Summary
Excitation-contraction (E-C) coupling is a term used to broadly describe the sequence of cellular events that starts with an electrical signal at the surface membrane of a muscle cell and which then ultimately leads to muscle contraction. Although the overall sequence is known, there remain many gaps in our understanding of the mechanisms involved not only related to normal muscle function but to how this function may be impaired by excessive exercise and disease. Many cellular metabolites contr ....Excitation-contraction (E-C) coupling is a term used to broadly describe the sequence of cellular events that starts with an electrical signal at the surface membrane of a muscle cell and which then ultimately leads to muscle contraction. Although the overall sequence is known, there remain many gaps in our understanding of the mechanisms involved not only related to normal muscle function but to how this function may be impaired by excessive exercise and disease. Many cellular metabolites contribute towards the normal control of muscle contraction, while others contribute to its impairment. Reactive oxygen species (ROS), which includes nitric oxide (NO) and related molecules, are metabolic factors often referred to as cellular oxidants. They are thought to have an essential role in controlling normal muscle function. Paradoxically, they are also implicated in the impairment of muscle function associated with fatigue, disease and aging. How these molecules both control normal muscle activity and also contribute to impairment of such function remains unclear. Thus, the central aim of this project is to identify the mechanisms by which the cellular oxidants, NO and other ROS, both control normal E-C coupling in skeletal muscle fibres and how they contribute to muscle fatigue. Clearly, understanding how skeletal muscle normally contracts is essential in order to better understand how muscle function can become impaired with exercise, disease and age. The work from this study will provide insight into both normal muscle physiology and how muscles fatigue and ultimately provide new methodologies and drugs that may combat fatigue, disease and age related changes to muscle function.Read moreRead less