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Molecular And Cellular Basis For Muscle Regeneration In Zebrafish.
Funder
National Health and Medical Research Council
Funding Amount
$541,104.00
Summary
Muscle repair occurs via the use of muscle stem cells, which provide skeletal muscle with its regenerative capacity. Muscle stem cells are particularly important in muscle diseases such as muscular dystrophies where muscle regeneration is an important factor in disease progression. We will identify the processes controlling muscle regeneration utilising zebrafish as a model organism. We hope this research will lead to an understanding of how muscle stem cells are generated.
Novel Transcriptional Regulation In Skeletal Muscle Development And Disease
Funder
National Health and Medical Research Council
Funding Amount
$344,592.00
Summary
It has been assumed that once genes are activated in a particular type of cell, they remain 'on'. From work described in this laboratory, we now know that gene activity may come and go. Instead of the analogy of a light switch that has been turned on and stays on, it appears that at least in muscle, gene activity is more like blinking lights. If you take an image of muscle tissue, which is just a snapshot in time, a gene may not appear to be activated if it was temporarily 'flashing off' at the ....It has been assumed that once genes are activated in a particular type of cell, they remain 'on'. From work described in this laboratory, we now know that gene activity may come and go. Instead of the analogy of a light switch that has been turned on and stays on, it appears that at least in muscle, gene activity is more like blinking lights. If you take an image of muscle tissue, which is just a snapshot in time, a gene may not appear to be activated if it was temporarily 'flashing off' at the time of viewing. This may occur in all tissue types, but it is more easily detected in muscle because the cell is large with many nuclei, rather than small with a single nucleus. Another reason why this phenomenon is more readily detectable in muscle cells is that they are very dynamic cells that can undergo fairly radical changes in shape. An actively growing or hypertrophying muscle cell may have all of its genes at a high pitch of transcriptional activity to support rapid growth. However, once a muscle cell has reached its appropriate size, then muscle genes switch to a flashing mode of transcription to maintain rather than build structures. SIGNIFICANCE: (1) This may be a fundamental mechanism of gene regulation that occurs in virtually all cell types. As such, our finding will open an area of research into the types of molecules involved in this novel mechanism. (2) Our studies will result in a better understanding of the mechanisms of muscle cell hypertrophy in response to excercise and drugs, as well as atrophy due to nerve damage or inherited muscle disease. (3) This mechanism may explain the expression of foreign DNA in muscle cells delivered via gene therapy approaches. Our findings could result in a more efficacious means of expressing the introduced gene that might require tricking the muscle fibre into believing that it is in a perpetual growth mode.Read moreRead less
Skeletal muscle responds to exercise or mechanical load, in a process known as hypertrophy. Hypertrophy is initiated by a population of immature muscle cells known as myoblasts which fuse to form myotubes, and then mature to form muscle fibers (differentiation). Many proteins involved in a cascade of activation and-or deactivation are important for regulating hypertrophy (hypertrophic signaling). Failure of skeletal muscle to induce hypertrophy can lead to muscle degeneration. The FHL proteins a ....Skeletal muscle responds to exercise or mechanical load, in a process known as hypertrophy. Hypertrophy is initiated by a population of immature muscle cells known as myoblasts which fuse to form myotubes, and then mature to form muscle fibers (differentiation). Many proteins involved in a cascade of activation and-or deactivation are important for regulating hypertrophy (hypertrophic signaling). Failure of skeletal muscle to induce hypertrophy can lead to muscle degeneration. The FHL proteins are highly expressed in skeletal muscle. FHL proteins are molecular scaffolds which direct assembly of protein complexes to form the muscle contraction machinery (sarcomere). We propose FHL proteins will initiate-regulate skeletal muscle hypertrophy. Increased levels of FHL1 correlate with skeletal muscle hypertrophy. However, it is unclear if increased FHL1 is alone sufficient to induce hypertrophy directly. We have genetically engineered mice to express elevated levels of FHL1 specifically in skeletal muscles (FHL1 transgenic mice) and these mice show muscle enlargement. FHL1 transgenic mice have larger muscle fibers and are >7-fold stronger than non-transgenic littermates. We are currently examining which cell signaling pathways are affected by elevated FHL1. We are also investigating the role of another family member FHL3 in the differentiation of immature myoblasts, a process essential for both embryonic and postnatal skeletal muscle (hypertrophy) development. In the cell nucleus, FHL2 regulates genes which control cell growth and death and increased nuclear levels of FHL2 been detected in prostate cancer biopsies. Recently we demonstrated that FHL2 binds and is sequestered from the nucleus, by a protein, filamin. We are investigating the FHL2-mediated regulation of genes in human melanoma cells, which due to gene mutation are devoid of filamin and will determine how this affects FHL2 function in muscle.Read moreRead less
A Single Fibre Approach To The Study Of Regulation Of Protein Synthesis In Skeletal Muscle
Funder
National Health and Medical Research Council
Funding Amount
$420,039.00
Summary
Skeletal muscle is the most abundant tissue in the human body and accounts for more than 40% of body weight. Loss of muscle mass is a major cause of frailty and loss of functionality in the elderly and is also a common feature of many chronic diseases such as cancer, HIV, arthritis and chronic heart failure. Changes in protein synthesis are intrinsically associated with alterations in muscle mass, which is integral to health, physical performance and independent living. In this project we aim to ....Skeletal muscle is the most abundant tissue in the human body and accounts for more than 40% of body weight. Loss of muscle mass is a major cause of frailty and loss of functionality in the elderly and is also a common feature of many chronic diseases such as cancer, HIV, arthritis and chronic heart failure. Changes in protein synthesis are intrinsically associated with alterations in muscle mass, which is integral to health, physical performance and independent living. In this project we aim to answer some important outstanding questions regarding the regulation of protein synthesis in mammalian skeletal muscle using a novel, single cell approach. Results obtained within the framework of the project will contribute to the understanding of the regulation of cellular and molecular events underpinning protein synthesis in muscle, which is critical for developing effective strategies of treatment and management of various medical conditions to prevent muscle wasting.Read moreRead less
Characterization Of The FHL Protein Family In Striated Muscle
Funder
National Health and Medical Research Council
Funding Amount
$500,750.00
Summary
This grant examines the role of a family of muscle proteins, called FHL proteins, in skeletal and heart muscle. Inherited muscular disorders such as muscular dystrophy and myopathies, cause muscle weakness, which may be profound and lead to premature death due to respiratory muscle failure, or cause mild weakness later in life. The proteins which are defective in these muscular dystrophies are structural muscle proteins, which link and stabilize the contractile fibres in muscle and protect the m ....This grant examines the role of a family of muscle proteins, called FHL proteins, in skeletal and heart muscle. Inherited muscular disorders such as muscular dystrophy and myopathies, cause muscle weakness, which may be profound and lead to premature death due to respiratory muscle failure, or cause mild weakness later in life. The proteins which are defective in these muscular dystrophies are structural muscle proteins, which link and stabilize the contractile fibres in muscle and protect the muscle from the stresses and damage resulting from repeated muscular contraction. We have identified that the FHL proteins, which are the focus of this grant application, bind to and potentially regulate muscle proteins, which have been shown to cause forms of muscular dystrophy and cardiomyopathy. Examination of these interactions will provide insights into the biological mechanism of these muscle disorders. Furthermore, one of these proteins, FHL1 is significantly increased in hypertrophic cardiomyopathy, heart muscle thickening, a major cause of sudden cardiac death in young adults. We are creating transgenic mice, which make increased levels of FHL1 protein in their heart muscle, to determine whether increased FHL1, by itself is sufficient to promote heart muscle thickening. These studies should lead to further understanding of the development of diseases of heart and skeletal muscle, which may lead to novel treatments in the future.Read moreRead less
Defining Mechanisms Of Follistatin-mediated Muscle Adaptation, For Treatment Of Frailty And Muscle-related Diseases
Funder
National Health and Medical Research Council
Funding Amount
$557,478.00
Summary
Physical frailty-weakness is one of the most common symptoms of serious illness and a key cause of death. I propose to study a new model of skeletal muscle growth, to learn more about the causes of wasting in muscle-related diseases. The work will identify cell mechanisms that cause loss of muscle strength, and will help develop novel treatment approaches to prevent or reverse physical frailty in illness. New therapies to combat frailty are vital to improve the health of our community.
Maintenance of skeletal muscle integrity is critical for normal locomotor function. During adulthood skeletal muscle mass and strength is progressively lost which leads to locomotor impairment common in the elderly. Loss of skeletal muscle may also contribute to functional impairment in patients with inherited disorders of the scaffolding connective tissue that hold muscle fibres together, such as Duchenne's dystrophy. Understanding the biology of muscle cell growth and responses to environmenta ....Maintenance of skeletal muscle integrity is critical for normal locomotor function. During adulthood skeletal muscle mass and strength is progressively lost which leads to locomotor impairment common in the elderly. Loss of skeletal muscle may also contribute to functional impairment in patients with inherited disorders of the scaffolding connective tissue that hold muscle fibres together, such as Duchenne's dystrophy. Understanding the biology of muscle cell growth and responses to environmental stresses such as exercise and ageing is, therefore, critical to healthy daily functioning. In preliminary studies we have defined a novel biochemical pathway which we believe underlies the ability of muscle to grow larger and stronger. In this application, we propose to rigorously evaluate the role of this pathway in muscle growth by experiments performed both with cell culture models and in animals. The findings of this study would have direct therapeutic benefit for a large number of major clinical conditions, such as heart failure, age-related muscular weakness and muscle diseases.Read moreRead less
Genetic Determinants Of Inherited Optic Neuropathies
Funder
National Health and Medical Research Council
Funding Amount
$249,750.00
Summary
Glaucoma is a slowly progressive visual disorder of the optic nerves often but not always associated with elevated pressure in the eyes. There is a strong genetic component. It is estimated to affect in excess of 60 million people worldwide with more than 6 million of those blind in both eyes. It is the second commonest cause of visual impairment in the developed world, and is present in up to 10% of the population by age 90. Numbers of affected patients in Australia are expected to double in th ....Glaucoma is a slowly progressive visual disorder of the optic nerves often but not always associated with elevated pressure in the eyes. There is a strong genetic component. It is estimated to affect in excess of 60 million people worldwide with more than 6 million of those blind in both eyes. It is the second commonest cause of visual impairment in the developed world, and is present in up to 10% of the population by age 90. Numbers of affected patients in Australia are expected to double in the next 30 years. Current methods of early detection and treatment are often inadequate, and associated visual loss is irreversible. There is a strong need for greater understanding of the disease process and new strategies to prevent and treat visual loss. Two less common causes of untreatable optic nerve blindness are Leber Hereditary Optic Neuropathy (LHON) and autosomal dominant optic atrophy (ADOA) which occur in younger age groups than most cases of glaucoma, and hence sufferers may experience substantial physical, emotional and economic hardship. Over a 10 year period we have seen large numbers of patients with all three eye conditions and have developed a powerful study to determine the genes which cause optic nerve blindness and their relative importance. The research is gathering momentum and the genetics of all 3 conditions are now partly understood. This project seeks to analyse a new major glaucoma gene (Optineurin) in our Australian population and to try to understand the way in which a number of genes interact to cause blindness in some patients but not others. This work will lead to greater understanding of these causes of blindness and is likely to lead to new screening tests to know who is at most risk, and the opportunity to develop and test new treatments targeted to the underlying genetic problem.Read moreRead less
IL-11 As A Novel Parietal Cell Cytokine That Blocks Gastric Acid Secretion And Causes Gastric Atrophy
Funder
National Health and Medical Research Council
Funding Amount
$524,820.00
Summary
Stomach cancer will kill a million people in the world in 2010, while in the western world the numbers of affectd indiviuduals are decreasing while in the in the developing world the opposite is the thus adding to the global health burden. Gastric atrophy is a pathological condition that always preceeds gastric cancer. This project aims to devlop our knowledge of the intitating events that allow atrophy to develop, thus informing us of novel ways of treating this condition before it bcomes cance ....Stomach cancer will kill a million people in the world in 2010, while in the western world the numbers of affectd indiviuduals are decreasing while in the in the developing world the opposite is the thus adding to the global health burden. Gastric atrophy is a pathological condition that always preceeds gastric cancer. This project aims to devlop our knowledge of the intitating events that allow atrophy to develop, thus informing us of novel ways of treating this condition before it bcomes cancerous.Read moreRead less