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
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
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
Understanding The Opposing Roles Of SWI-SNF In The Control Of Gene Programs For Pathological Cardiac Hypertrophy
Funder
National Health and Medical Research Council
Funding Amount
$476,258.00
Summary
Following the success in decoding human genome, i.e. DNA sequence, a major task is to understand how the activity of genes with consequent changes in respective proteins. As proteins are an important component for cell structure and function, such changes in quantity and quality of proteins will play a pivotal role to affect disease development and progression.
Transcriptional Regulatory Complexes Associated With Cardiac Hypertrophy
Funder
National Health and Medical Research Council
Funding Amount
$474,517.00
Summary
Following the success in decoding human genome, i.e. DNA sequence, a major task is to understand how the activity of genes with consequent changes in respective proteins. As proteins are an important component for cell structure and function, such changes in quantity and quality of proteins will play a pivotal role to affect disease development and progression. It has been well known that a group of genes are altered (up or down) in the heart under conditions such as heart muscle overgrowth (ie ....Following the success in decoding human genome, i.e. DNA sequence, a major task is to understand how the activity of genes with consequent changes in respective proteins. As proteins are an important component for cell structure and function, such changes in quantity and quality of proteins will play a pivotal role to affect disease development and progression. It has been well known that a group of genes are altered (up or down) in the heart under conditions such as heart muscle overgrowth (ie hypertrophy), aging or of abnormal beating function. The reasons for such altered gene activity remain poorly understood. Although recent studies from research on genetics or cancer have revealed the important role of the DNA and DNA-bound proteins (called histone) in the control of gene activity, this has rarely been studied in the heart. In this project, we will test our hypothesis that DNA-histone structure is a key factor that control gene activities in ageing and diseased heart. This proposal is supported by our recent findings showing that in the hypertrophied heart, such DNA-histone structure did alter in such a way that fits well with alterations in gene activity. We have planned a series of studies to test this hypothesis in a systematic fashion. A number of sophisticated and cutting-edge techniques and experimental models of heart hypertrophy will be used. We will analyse changes in activities of a number of selected genes in the heart and also analyse changes in DNA-histone structures and chemical modifications at particular regions. These changes will then be linked together. We will also explore the possibility of modulating DNA-histone structure, thereby controlling the degree of cardiac hypertrophy. This project is the joint efforts of scientists with substantial experience in research on gene activity and heart diseases, and is highly likely to generate novel information to and hold significant therapeutic potential.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
We have discovered a single tumour factor which causes cancer cachexia, a wasting condition that is one of the worst complications of malignancy, for which there is no current effective treatment. We have developed antibodies which effectively block this condition in preclinical models and have produced human/humanised version of this. This application is to characterise these human antibodies to allow us proceed to clinical trials.
Can Exercise Early After Spinal Cord Injury Prevent Deterioration Of Muscle And Bone?
Funder
National Health and Medical Research Council
Funding Amount
$775,049.00
Summary
Spinal cord injury leads to a profound deterioration of the muscles and bones in the paralysed limbs. This project will examine the effects of exercising the paralysed limbs as early as possible after injury to prevent muscle and bone loss rather than restoring the tissues once changes have occurred. The time course and mechanisms underlying the microstructural decay of bone over the first year after injury will also be examined to provide a basis for determining fracture risk in this group.
Structural And Functional Consequences Of Left Ventricular Hypertrophy Regression.
Funder
National Health and Medical Research Council
Funding Amount
$293,036.00
Summary
Left ventricular hypertrophy (LVH) is a thickening of the heart muscle walls that occurs in a variety of cardiovascular diseases, including high blood pressure, coronary artery disease, cardiac valve disorders and heart dilatation. The presence of LVH increases the risk of developing heart attacks, heart failure and death. Treatment of these disorders is a major component of our escalating health-care costs. Consequently, reversal of LVH may have significant benefits to individual patients and s ....Left ventricular hypertrophy (LVH) is a thickening of the heart muscle walls that occurs in a variety of cardiovascular diseases, including high blood pressure, coronary artery disease, cardiac valve disorders and heart dilatation. The presence of LVH increases the risk of developing heart attacks, heart failure and death. Treatment of these disorders is a major component of our escalating health-care costs. Consequently, reversal of LVH may have significant benefits to individual patients and society in general. We propose to develop a mouse model of an inherited form of LVH that is caused by gene mutations in heart muscle proteins. This model will enable us to study in detail the disease processes that cause LVH and the effects of reversing LVH. This information will be invaluable for determining the best ways of treating patients with LVH.Read moreRead less