All cells have a characteristic shape (morphology), which is intrinsic to cellular function. A blood cell is designed to move in a liquid medium whereas a muscle cell is optimised for physical movement of attached bones. We are studying the mechanisms which control cell shape. We focus on the components of the cell skeleton (cytoskeleton) which are implicated in the regulation of shape. In particular, we study the actin based microfilament system. We have previously shown that two types of these ....All cells have a characteristic shape (morphology), which is intrinsic to cellular function. A blood cell is designed to move in a liquid medium whereas a muscle cell is optimised for physical movement of attached bones. We are studying the mechanisms which control cell shape. We focus on the components of the cell skeleton (cytoskeleton) which are implicated in the regulation of shape. In particular, we study the actin based microfilament system. We have previously shown that two types of these components of the cytoskeleton are able to control the structure of cells. In addition, we have found that variants of these two components (called isoforms) are used to build structures in different parts of cells. This has led us to think about the anatomy of cells and tissues in a new way. In some ways its like building a city. You create different kinds of buildings to suit their purpose. Each building uses a combination of building blocks which suit the structural demands of rooms and the overall building. In this study we are proposing to identify the specific job that one of these types of building blocks must play in order to allow normal cell growth and embryo development. To do this, we plan to change these genes in mice and then examine the impact on cell and tissue anatomy. This promises to contribute to the conversion of anatomical science and pathology from descriptive to experimental-mechanistic disciplines. This in turn will lead to a new tool set of diagnostic agents for the pathologist and the development of drugs which target specific functions of the cytoskeleton.Read moreRead less
Mechanism Of Action Of Dynamin Ring Stabilizer Compounds Controlling The Actin Cytoskeleton
Funder
National Health and Medical Research Council
Funding Amount
$659,360.00
Summary
We will test our hypothesis that ring stabilizer (RS) compounds we invented may become future proteinuric kidney disease therapeutics. The global epidemic of kidney disease eludes present treatments. Dysfunction of podocyte cells accounts for 90% of end-stage kidney diseases. Our pilot data shows that our ring stabilizer compounds restore podocyte function in vitro and kidney function in animal models. We aim to understand their mechanism of action.
Differential Regulation Of Human Tyrosine Hydroxylase Isoforms And The Development Of Parkinson's Disease
Funder
National Health and Medical Research Council
Funding Amount
$325,591.00
Summary
Parkinson's disease is a common neurodegenerative disease whose major feature is loss of a dopamine containing nerves in a part of the brain called the substantia nigra. Loss of nerves within the substantia nigra is not uniform, but firstly and primarily affects the ventral cells, suggesting that particular dopaminergic neurons are more vulnerable to the disease process. A key to understanding Parkinson's disease would be to work out why these cells are more susceptible to degeneration than othe ....Parkinson's disease is a common neurodegenerative disease whose major feature is loss of a dopamine containing nerves in a part of the brain called the substantia nigra. Loss of nerves within the substantia nigra is not uniform, but firstly and primarily affects the ventral cells, suggesting that particular dopaminergic neurons are more vulnerable to the disease process. A key to understanding Parkinson's disease would be to work out why these cells are more susceptible to degeneration than other dopaminergic cells in the brain. Tyrosine hydroxylase controls the rate of dopamine synthesis. Humans are unique in that they contain four isoforms of tyrosine hydroxylase and therefore they have the potential to alter the regulation of dopamine synthesis in ways that other species do not. Recent developments in our laboratories have suggested that particular isoforms of tyrosine hydroxylase may have either a role in the susceptibility of dopaminergic neurons to degeneration in Parkinson's disease or a role in the timing of the symptoms of the disease. We have demonstrated differences in the distribution of the human TH isoforms within the substantia nigra, with certain isoforms being more prevalent in the susceptible ventral cells. We have also shown that there are major differences in the regulation of the four human tyrosine hydroxylase isoforms. Some isoforms will be more sensitive to conditions that occur with high frequency stimulation of neurons and some to low frequency sustained stimulation. This would provide a mechanism by which differential distribution of the human TH isoforms would result in altered dopamine synthesis in different parts of the human brain and this may in turn lead to either increased susceptibility to, or earlier appearance of symptoms of, Parkinson's disease.Read moreRead less
Dissecting The Molecular Basis Of Actin Filament Disassembly In The Malaria Parasite
Funder
National Health and Medical Research Council
Funding Amount
$576,716.00
Summary
Cell movement by the malaria parasites is fundamental to parasite infection and disease. However, whilst core components of the parasite motor driving movement are known, little is understood about their regulation, in particular actin – the dynamic force behind all parasite motility. Here by dissecting the role of actin-depolymerizing-factor-1, an essential parasite actin regulator, we hope to reveal one of the central processes that underlies motility and develop it into a potential drug targe ....Cell movement by the malaria parasites is fundamental to parasite infection and disease. However, whilst core components of the parasite motor driving movement are known, little is understood about their regulation, in particular actin – the dynamic force behind all parasite motility. Here by dissecting the role of actin-depolymerizing-factor-1, an essential parasite actin regulator, we hope to reveal one of the central processes that underlies motility and develop it into a potential drug target.Read moreRead less