Innovative Use Of Hydrogel Technology To Recapitulate And Investigate Cardiac Pathology.
Funder
National Health and Medical Research Council
Funding Amount
$716,162.00
Summary
Hypertrophic cardiomyopathy is the leading cause of sudden death in the young. No treatment exists that can reverse or prevent it, primarily because the underlying mechanisms of the disease have not been fully elucidated. I will use innovative hydrogel technology to simulate the disease state. I will use this as a tool to identify the mechanisms involved with development of the disease. This will enable identification of potential therapeutic targets for prevention of the disease.
Cytoskeletal Remodeling Of The Erythrocyte During Malaria Parasite Invasion
Funder
National Health and Medical Research Council
Funding Amount
$559,807.00
Summary
Malaria parasites cause profound human disease through infection of the red blood cell. How parasites break into the red cell is incompletely understood. Foremost, the parasite must induce radical changes in its structural integrity to enter, but to date no study has been able to precisely map these cellular events. In this research program we aim to dissect the entire process using state-of-the-art imaging, molecular biology and proteomics to shine new light on this key step in malaria disease ....Malaria parasites cause profound human disease through infection of the red blood cell. How parasites break into the red cell is incompletely understood. Foremost, the parasite must induce radical changes in its structural integrity to enter, but to date no study has been able to precisely map these cellular events. In this research program we aim to dissect the entire process using state-of-the-art imaging, molecular biology and proteomics to shine new light on this key step in malaria disease establishment.Read moreRead less
The Role Of The Actomyosin Cytoskeleton In T Cell-mediated Anti-tumour Immunity
Funder
National Health and Medical Research Council
Funding Amount
$616,950.00
Summary
T cells, specialised immune cells, are crucial in the defence against tumours. In order to reach cancerous target cells, T cells must enter tumour tissues from the blood stream and then effectively migrate in the extravascular space. This application aims to uncover the role of the cytoskeleton, a group of molecules driving cell shape change and motility, in the efficient execution of T cell anti-tumour function. These studies will aid the development of improved immunotherapies against cancer.
A Novel Cytoskeletal Structure In Muscle Is Associated With Muscular Dystrophy
Funder
National Health and Medical Research Council
Funding Amount
$371,250.00
Summary
A NEW PROTEIN NETWORK IN MUSCLE IS ASSOCIATED WITH MUSCLE DISEASE An intricate protein network connects the contracting mechanism of a muscle to the surrounding cell membrane. Disruption of this connection is one of the known causes of muscular dystrophy. For many patients however the cause of the disease is unknown. We have identified a new region within this protein network that is also associated with muscle disease in mice. A number of proteins that are involved in transmitting chemical mess ....A NEW PROTEIN NETWORK IN MUSCLE IS ASSOCIATED WITH MUSCLE DISEASE An intricate protein network connects the contracting mechanism of a muscle to the surrounding cell membrane. Disruption of this connection is one of the known causes of muscular dystrophy. For many patients however the cause of the disease is unknown. We have identified a new region within this protein network that is also associated with muscle disease in mice. A number of proteins that are involved in transmitting chemical messages from one part of the muscle cell to another are found at this same location. It is possible that disruption of these messages may lead to muscle disease. This project aims to establish the nature of the relationship between the proteins found in this newly identified region of the protein network and muscle diseases such as muscular dystrophy, in both animal models and in humans. We expect that this project may identify new markers for identifying the cause of muscle diseases in some patients and lead to better hopes for an eventual cure.Read moreRead less
ISG60, A Novel Interferon-induced Protein: Cell Growth Inhibitory Actions
Funder
National Health and Medical Research Council
Funding Amount
$197,030.00
Summary
The interferons are signaling molecules produced by cells as part of an early warning sytsem to alert nearby tissue cells and immune cells to defend themselves against an impending viral attack or aberrant growth of cells. We have discovered ISG60, a new member of a group of proteins called the ISG54 family. The production of this family of proteins is turned on in all cells responding to the interferons. Exactly what the members of the protein family do within cells remains to be established. H ....The interferons are signaling molecules produced by cells as part of an early warning sytsem to alert nearby tissue cells and immune cells to defend themselves against an impending viral attack or aberrant growth of cells. We have discovered ISG60, a new member of a group of proteins called the ISG54 family. The production of this family of proteins is turned on in all cells responding to the interferons. Exactly what the members of the protein family do within cells remains to be established. However, by preparing cells which produce the ISG60 protein, we have found that it severely affects their growth, slowing the growth rate down and making the cells divide abnormally to become large, containing many nuclei and others dying. We propose that ISG60 binds to the structures involved in cell division and we have preliminary evidence that ISG60 interacts with an important protein involved in cell regulation, the retinoblastoma protein (pRb). The aim of this project is to more fully understand the role of ISG60 in cells. In particular, we aim to determine if ISG60 interacts with other important proteins inside cells. We shall explore the relationship of ISG60 function inside cells in greater detail as it should provide new insight into ways in which cell growth is regulated. This study will also provide insight into how the slowing of cell growth makes the cells less suitable for viral infection and reproduction, as well as providing new approaches for preventing the growth of cancer cells.Read moreRead less
Function Of The Flightless Protein In Wound Repair And Scar Formation In Skin
Funder
National Health and Medical Research Council
Funding Amount
$472,750.00
Summary
Scarring is the inevitable outcome of wound repair and can cover a spectrum of conditions, from normal fine lines to unsightly, restrictive and deforming scars. Each year in the world over 100 million patients acquire scars, primarily from surgical procedures. Many of these scars cause considerable problems. Over 4 million burn scars occur every year, 70% of them in children. Poor wound healing is a major clinical problem and can result in loss of movement and deformity. These are especially imp ....Scarring is the inevitable outcome of wound repair and can cover a spectrum of conditions, from normal fine lines to unsightly, restrictive and deforming scars. Each year in the world over 100 million patients acquire scars, primarily from surgical procedures. Many of these scars cause considerable problems. Over 4 million burn scars occur every year, 70% of them in children. Poor wound healing is a major clinical problem and can result in loss of movement and deformity. These are especially important considerations for children, where their growth places extra demands on healing wounds and grafts, necessitating regular surgical adjustment. Scarring is an area of largely unmet medical need and development of new treatment strategies would have significant impact on public health. Changes in cell adhesion, shape and movement are important processes in wound repair. A framework of filaments, much like guy-ropes that support a tent, help coordinate these events. Remodelling of these filaments, shortening or extending them and making new connections, allows cells to change shape and respond to stimuli. This is a crucial event in repairing wounds and the proteins that perform this are fundamentally important to wound repair. We have discovered a protein in skin, known as Flightless, that is involved in this filament remodelling process. The goal of this project is to determine what Flightless does in wound repair. By changing the amount of this protein and comparing its effect in non-scarring and scarring animal wound healing models we can gain insight into its role in wound healing and scar formation in humans. The development of new animal models in this research and the discovery of the role of Flightless in wound repair will provide exciting new opportunities to improve wound repair and reduce scarring, with significant impact on public health.Read moreRead less
The Influence Of Alpha Actinins On Human Performance
Funder
National Health and Medical Research Council
Funding Amount
$542,500.00
Summary
There is a wide variation in skeletal muscle function in the general population. At one end of the spectrum are elite athletes who excel in a specialised area of sprint, power or endurance performance, while at the other end of the spectrum are individuals with muscle weakness due to inherited muscle disease. Part of this variation in human muscle performance is due to the genetic makeup of the individual. For example, world class sprinters have muscles which are genetically predisposed to gener ....There is a wide variation in skeletal muscle function in the general population. At one end of the spectrum are elite athletes who excel in a specialised area of sprint, power or endurance performance, while at the other end of the spectrum are individuals with muscle weakness due to inherited muscle disease. Part of this variation in human muscle performance is due to the genetic makeup of the individual. For example, world class sprinters have muscles which are genetically predisposed to generate maximal force at high speed. Similarly, the severity of muscle disease in an affected individual is influenced, in part, by other genes that affect normal muscle performance. The genes responsible for normal variations in muscle function in humans are unknown. The alpha-actinins are structural components of skeletal muscle. The two forms of alpha-actinin in skeletal muscle interact with a number of proteins involved in human muscle disease and thus likely contribute to the severity of muscle weakness in affected patients. Alpha-actinin-3 is present only in fast (type 2) fibres - the muscle fibres responsible for perfomance at high speed. We have identified a genetic change that results in absence of this protein in 1 in 5 people in the general population, without causing disease. We now have evidence that this genetic change, and hence whether or not muscle contains alpha-actinin-3, influences muscle performance in elite athletes. We will now use a variety of approaches to study the alpha-actinins in normal and diseased skeletal muscle. We will study the effect of changes (mutations) in the alpha-actinins in the muscle cells grown in the laboratory and in animal models. This work will impact on our understanding of how normal skeletal muscle functions, and the factors that influence human diversity in the general population.Read moreRead less
REGULATION OF MICROTUBULE DYNAMICS BY LIM KINASE1 (LIMK1)
Funder
National Health and Medical Research Council
Funding Amount
$386,020.00
Summary
Disseminated cancer, unlike the localized disease, can rarely be cured by drug therapy. We have found that LIM kinase (LIMK1), a protein that was discovered in our laboratory, plays an important role in controlling the ability of tumour cells to spread, a process called metastasis. Thus, this protein becomes an important target for the development of new drug therapies to prevent the spread of cancer. We have found that LIMK1 is very important in controlling the polymerisation of one of the most ....Disseminated cancer, unlike the localized disease, can rarely be cured by drug therapy. We have found that LIM kinase (LIMK1), a protein that was discovered in our laboratory, plays an important role in controlling the ability of tumour cells to spread, a process called metastasis. Thus, this protein becomes an important target for the development of new drug therapies to prevent the spread of cancer. We have found that LIMK1 is very important in controlling the polymerisation of one of the most abundant molecules in the cell, actin. We have now preliminary data to show that LIMK1 also controls another important cellular protein, tubulin. Changes in tubulin polymerisation are of extreme importance for cell division and drugs affecting the state of tubulin are very potent as anti-cancer drugs. The goals of this research are: (1) To confirm that LIMK1 regulates the polymerisation of tubulin and (2) To demonstrate that LIMK1 regulates tubulin polymerisation by controlling the activity of p25, a protein involved in tubulin polymerisation that is modified by LIMK1. The results from this research will be highly significant because LIMK1 is a novel drug development target. Drugs that inhibit this protein may block the ability of tumours to invade and metastasise. Therefore, we have to identify the other functions of LIMK1 to eliminate the possibility that drugs that inhibit LIMK1 and metastasis don't affect other organs and cells in the body. New molecules regulated by LIMK1 may also be suitable targets for drug development because through their inhibition we may also regulate other LIMK1 activities and possibly metastasis.Read moreRead less
The Influence Of Alpha Actinins On Human Performance In Health And Disease
Funder
National Health and Medical Research Council
Funding Amount
$480,989.00
Summary
We have identified a common genetic variation that results in absence of the fast muscle fibre protein, a-actinin-3, in over 1 billion people worldwide. Loss of a-actinin-3 influences elite athletic performance and skeletal muscle function in the general population by altering efficiency of muscle metabolism. We will now study mice and humans to determine how a-actinin-3 deficiency influences normal muscle function with age, response to exercise and the severity of human muscle disease.