Biomathematical Analysis Of Cell Invasion: Migration Of Neural Crest Cells To Form The Enteric Nervous System
Funder
National Health and Medical Research Council
Funding Amount
$449,484.00
Summary
Extending scientific studies to a mathematical level is the way to produce deep understanding and control. Mathematics has been applied less to biology, particularly the biology of development, than to other branches of science, no doubt due to the innate complexity and technical difficulties of seeing and measuring what is actually going on. Labelling, imaging and computational tools to visualise biological processes are only now becoming available. To build our bodies during embryonic developm ....Extending scientific studies to a mathematical level is the way to produce deep understanding and control. Mathematics has been applied less to biology, particularly the biology of development, than to other branches of science, no doubt due to the innate complexity and technical difficulties of seeing and measuring what is actually going on. Labelling, imaging and computational tools to visualise biological processes are only now becoming available. To build our bodies during embryonic development, cells must move; this is called cell migration. The same process occurs throughout life in wound repair. Uncontrolled migration is the hallmark of malignant cancers, where it is called invasion. The molecular mechanisms in cells that allow them to move are just beginning to be understood. However, the big questions determining the general rules of migration are more difficult to approach. Here are some examples of such questions. When to migrate? Where to migrate to? Which pathways? How many cells to migrate? How far? How fast? How to stop? Such simple questions are still unanswered. We are pioneering a novel and unique approach combining imaging of real cells migrating in real tissues (digital time-lapse movies) with mathematical modelling to understand the driving forces of cell migration-invasion. This technology is here applied to a particular example of cell migration where precursor nerve cells migrate all the way along the length of the gastro-intestinal tract in early development. This process gives rise to fatal birth defects associated with migration failure. The development of the nervous system in the gut has features in common with all other migrations and invasions, normal and pathological. A much more profound knowledge of the big picture of the developmentally and clinically crucial process of cell migration-invasion will emerge from this marriage of biological experimentation and mathematical modelling.Read moreRead less
Dissecting The Molecular Mechanisms Driving Cell Migration During Neurulation Triggered By The Netrin Receptor, Neogenin
Funder
National Health and Medical Research Council
Funding Amount
$432,750.00
Summary
In humans, abnormalities in brain and spinal cord formation during early embryogenesis result in congenital syndromes such as spina bifida and anencephaly. These defects occur at a rate of 1-1000 pregnancies and are therefore a major contributor to pre- and perinatal deaths. In the early embryo, the brain and spinal cord begin as a hollow tube of cells (the neural tube) that subsequently expands into the complex structures seen at birth. It is known that the neural tube is formed by a complex pr ....In humans, abnormalities in brain and spinal cord formation during early embryogenesis result in congenital syndromes such as spina bifida and anencephaly. These defects occur at a rate of 1-1000 pregnancies and are therefore a major contributor to pre- and perinatal deaths. In the early embryo, the brain and spinal cord begin as a hollow tube of cells (the neural tube) that subsequently expands into the complex structures seen at birth. It is known that the neural tube is formed by a complex process in which early neural cells migrate toward the midline of the embryo and subsequently coalesce. This project seeks to determine the function of one molecular signaling pathway (the neogenin pathway) that has been implicated in driving these cell migration events. We will initially use the frog, Xenopus laevis, as our embryonic model since the developmental processes that form the Xenopus neural tube closely parallel those ocurring in the human embryo. This model will allow us to identify the molecules in the neogenin signaling pathway. We will also create mice that carry a mutation in the neogenin gene so that we can study neogenin function in the mammal. We anticipate that these studies will provide important insights into the development of the central nervous system and also into the aberrant molecular processes underlying neural tube defects in man.Read moreRead less
Cortical Plasticity And Fine Motor Skills In Older Adults
Funder
National Health and Medical Research Council
Funding Amount
$244,255.00
Summary
Even in healthy individuals, the ageing process is usually associated with a progressive reduction in the performance of various motor skills, such as writing, placing keys in keyholes and fastening buttons. These deficits in manual performance may be due to an age-related decline in the ability of the brain to modify its connections (plasticity) when learning new motor skills. This brain plasticity is a fundamental property of the nervous system, where it is critical for learning and memory, bu ....Even in healthy individuals, the ageing process is usually associated with a progressive reduction in the performance of various motor skills, such as writing, placing keys in keyholes and fastening buttons. These deficits in manual performance may be due to an age-related decline in the ability of the brain to modify its connections (plasticity) when learning new motor skills. This brain plasticity is a fundamental property of the nervous system, where it is critical for learning and memory, but is also important for recovery from brain injury. The goal of the proposed studies is to examine the extent of brain plasticity when performing fine motor skills in older adults, and relate this to motor performance and learning in the elderly. We will use three complementary approaches that will employ novel techniques of magnetic brain stimulation to achieve this goal. These studies will be the first to ascertain a link between deficits in brain plasticity and impaired manual performance in older adults. Furthermore, these studies will be the first to examine interventions designed to promote brain plasticity and motor performance in older adults. Because the majority of patients requiring neurological rehabilitation are in an older age group, it is important to understand the extent of brain plasticity in the elderly. This new information may ultimately lead to innovative therapeutic or rehabilitation strategies to retain or improve fine motor skills in the elderly and promote functional recovery from brain injury.Read moreRead less
Dissecting The Molecular Mechanisms Behind Actin Filament Disassembly - An Essential Process In Malaria Parasite Cell Movement
Funder
National Health and Medical Research Council
Funding Amount
$311,860.00
Summary
The malaria parasite’s survival is reliant on efficient cell movement - a process that depends on the remodeling of the parasite actin cytoskeleton. The aim of this project is to understand how the actin cytoskeleton is disassembled when the parasite moves and to dissect the role of a key parasite protein, PfADF1, in the process. This project will elucidate fundamental insights into a key aspect of malaria parasite biology and, significantly, will shed light on how parasite movement can be inhib ....The malaria parasite’s survival is reliant on efficient cell movement - a process that depends on the remodeling of the parasite actin cytoskeleton. The aim of this project is to understand how the actin cytoskeleton is disassembled when the parasite moves and to dissect the role of a key parasite protein, PfADF1, in the process. This project will elucidate fundamental insights into a key aspect of malaria parasite biology and, significantly, will shed light on how parasite movement can be inhibited.Read moreRead less
Control Of Mastication By Periodontal Mechanoreceptors In Man
Funder
National Health and Medical Research Council
Funding Amount
$169,990.00
Summary
Despite the importance in chewing and speech, very little is known regarding the fine control of jaw muscles. A thorough understanding of the control of the jaw muscles is at the base of improved diagnosis and treatment of many chewing disorders. For example: We still do not understand the causes of the jaw muscle-joint pain disorder (temporomandibular dysfunction) which accounts for about 5 % of total dental patients. The current treatments, including pain killers, night plates and massage cure ....Despite the importance in chewing and speech, very little is known regarding the fine control of jaw muscles. A thorough understanding of the control of the jaw muscles is at the base of improved diagnosis and treatment of many chewing disorders. For example: We still do not understand the causes of the jaw muscle-joint pain disorder (temporomandibular dysfunction) which accounts for about 5 % of total dental patients. The current treatments, including pain killers, night plates and massage cure only about half of all patients. Improved diagnosis and treatment techniques require more precise elaboration of the neural and muscular mechanisms of chewing. Why do the chewing forces in toothless individuals, despite well fitting dentures, fall to about 20 % of the value in teethed individuals? Do jaw muscles in these subjects weaken because they get less feedback from the receptors around the teeth? How does the chewing force automatically adjust to overcome sudden or gradual changes in the characteristics of foodstuff? Although bite to bite changes in the chewing force is observed in subjects with natural teeth, no such changes occur in toothless subjects or subjects chewing with implanted bridges. How do the receptors adjust the activation of jaw muscles so that bite force is applied in the right direction and right amount at each bite? The aim of this study is to define the importance of the periodontal mechanoreceptors (tiny nerve cells that are situated between the roots of the teeth and the jaw bone that signal bite force to the brain) in the control of jaw muscles. This study will, therefore, illustrate the importance of keeping the teeth and gums healthy for the development of strong, smooth and well-controlled chewing forces, and potentially create opportunities to improve chewing (and thereby quality of life) in toothless individuals or those experiencing other difficulties in chewing.Read moreRead less
The Australian Parkinson's Project - Uncovering Genetic Risk Factors For Sporadic PD
Funder
National Health and Medical Research Council
Funding Amount
$768,546.00
Summary
Parkinson s disease (PD) is a progressively disabling movement disorder afflicting many elderly Australians. It is caused by the degeneration of specific nerve cells in the brain that produce certain chemicals and patients suffer from an inability to move fluently (or ultimately at all). At present we do not know what triggers this neurodegeneration, but it is believed that complex interactions between inherited (genetic) and environmental factors contribute significantly to the phenomenon. This ....Parkinson s disease (PD) is a progressively disabling movement disorder afflicting many elderly Australians. It is caused by the degeneration of specific nerve cells in the brain that produce certain chemicals and patients suffer from an inability to move fluently (or ultimately at all). At present we do not know what triggers this neurodegeneration, but it is believed that complex interactions between inherited (genetic) and environmental factors contribute significantly to the phenomenon. This project aims to learn more about these complex interactions and their association with PD. People with PD and unaffected individuals will be recruited from throughout Australia and we will look for specific combinations of genetic, environmental and lifestyle factors that either increase or decrease an individual's risk for PD. This research will identify the most common dominant genetic and environmental influences for PD in Australia, enabling scientists to focus on the most relevant biological pathways to target therapeutically.Read moreRead less
Reconsideration Of The Mechanisms Underlying Movement Changes With Pain
Funder
National Health and Medical Research Council
Funding Amount
$401,361.00
Summary
Pain changes the way we move. Although undisputed, there is a surprising lack of agreement regarding the underlying mechanisms. This project involves an innovative mix of neurophysiological methods to investigate how the drive to muscle cells from the nervous system is altered during pain. We aim to resolve the perplexing problem of how pain changes our ability to activate muscle. Our findings are likely to provide a clear understanding of the underlying mechanisms and guide rehabilitation.