E-Cadherin Endocytosis In Morphogenesis: Recycling And Growth Factor Induced Uptake.
Funder
National Health and Medical Research Council
Funding Amount
$498,088.00
Summary
E-cadherin is a cell-cell adhesion protein expressed in all epithelia with essential roles in establishing cell polarity and in tissue patterning during development. In the adult, E-cadherin functions to maintain epithelial integrity. E-cadherin is also a vital tumour suppressor, protecting cells against metastatic transformation. Our earlier studies showed that E-cadherin is constantly moved, or trafficked, to and from the surface of epithelial cells. The endocytosis or internalisation of cell ....E-cadherin is a cell-cell adhesion protein expressed in all epithelia with essential roles in establishing cell polarity and in tissue patterning during development. In the adult, E-cadherin functions to maintain epithelial integrity. E-cadherin is also a vital tumour suppressor, protecting cells against metastatic transformation. Our earlier studies showed that E-cadherin is constantly moved, or trafficked, to and from the surface of epithelial cells. The endocytosis or internalisation of cell surface E-cadherin serves to regulate its role in adhesion. More recently, we and others have shown that E-cadherin is endocytosed in response to growth factors, in conjunction with the activated growth factor receptors themselves. E-cadherin can influence the trafficking and signaling of these receptor tyrosine kinases. This joint endocytosis is an elegant mechanism for the simultaneous downregulation of cell adhesion and activation of signaling for cell growth and motility. The growth and differentiation of epithelial cells during tissue patterning or morphogenesis relies critically on these endocytic pathways. Our research is aimed at defining the endosomes and cellular machinery involved in E-cadherin-receptor endocytosis, moreover we will pursue initial findings suggesting that there are different pathways and fates for E-cadherin endocytosed at the behest of different growth factors. We will study endocytosis during the processes of epithelial cyst formation and tubulation of cysts as an in vitro model for mammalian morphogenesis. These studies will provide important and novel information for understanding the roles of E-cadherin in adhesion and in growth factor signaling during epithelial morphogenesis. Ultimately these findings will be of relevance to epithelial development and the prevention of cancer.Read moreRead less
Polarized Trafficking Of E-cadherin In Epithelial Cells.
Funder
National Health and Medical Research Council
Funding Amount
$515,564.00
Summary
The cell adhesion protein E-cadherin is expressed in all epithelial tissues of the body where it has essential functions during development and in the adult in establishing and maintaining polarized cell monolayers. E-cadherin is also a vital tumour suppressor, its normal function guarantees that cells or even early tumours cannot metastasise; in contrast E-cadherin is always lost or malfunctions in malignant tumours. Earlier studies showed that E-cadherin is constantly moved, or trafficked, to ....The cell adhesion protein E-cadherin is expressed in all epithelial tissues of the body where it has essential functions during development and in the adult in establishing and maintaining polarized cell monolayers. E-cadherin is also a vital tumour suppressor, its normal function guarantees that cells or even early tumours cannot metastasise; in contrast E-cadherin is always lost or malfunctions in malignant tumours. Earlier studies showed that E-cadherin is constantly moved, or trafficked, to and from the surface of epithelial cells. This trafficking has dual roles, firstly in delivering newly-made E-cadherin to the surface where it functions and secondly, in regulating its adhesive function. Our research in this project is focussed on the molecules and intracellular compartments that control the delivery of E-cadherin to the cell surface. E-cadherin must be sorted in order to be delivered to the correct side of the cell. Having previously discovered the sorting signal in E-cadherin, we will now identify the cognate adaptor protein(s) that accomplish this sorting. New imaging techniques allow us to study protein trafficking inside live cells. Such studies have recently revealed that E-cadherin passes through a recycling endosome compartment on its way to the cell surface. This unexpected route, and the structure and role of the recycling endosome will now be studied in detail in live cells. Finally we will compare the sorting and trafficking of E-cadherin with the closely-related N-cadherin protein, to determine whether there are inherent differences in their trafficking that could explain their opposite roles in tumour cells, where N-cadherin is substituted for E-cadherin and allows metastatic behaviour. These studies will provide important information for understanding the adhesive and tumour suppressive roles of E-cadherin. In addition our findings will generate information fundamental to our understanding of cell polarity and protein sorting.Read moreRead less
Recycling Endosomes Governing Cell Polarity And Cytokine Secretion.
Funder
National Health and Medical Research Council
Funding Amount
$958,412.00
Summary
Cytokines are chemical messengers released by cells to mount inflammatory responses to fight infections. The timing and direction of cytokine release must be tightly regulated. We investigate the cellular compartments and molecules that control cytokine secretion using sophisticated live cell imaging. Uncontrolled cytokine release is the main cause of ongoing inflammation in arthritis and inflammatory bowel disease and our studies aim to identify cellular targets for new drug development.
Investigating Post-transcriptional Gene Regulation In Cancer
Funder
National Health and Medical Research Council
Funding Amount
$645,205.00
Summary
In this program, I will enhance our understanding of cancer gene regulation and provide novel avenues for the treatment of aggressive tumours. Using own data and that from collaborators, I will determine patterns of gene regulation in blood cancers and identify markers that predict disease outcome. I aim to understand how gene regulation can transform healthy cells into tumour cells and whether personalised treatment can kill tumour cells more effectively and prevent relapse and metastasis.
Protecting cereal grain development at high temperatures. This project aims to investigate new temperature-responsive factors that regulate cereal grain development to protect grain production under heat stress. The new research will leverage international collaborations with access to cutting-edge genetic and technological resources, and refine novel X-ray imaging techniques in Australia, to observe how temperature affects flower structure and function in barley and rice. Favourable mutations t ....Protecting cereal grain development at high temperatures. This project aims to investigate new temperature-responsive factors that regulate cereal grain development to protect grain production under heat stress. The new research will leverage international collaborations with access to cutting-edge genetic and technological resources, and refine novel X-ray imaging techniques in Australia, to observe how temperature affects flower structure and function in barley and rice. Favourable mutations that optimise plant yield and fitness will be defined and explored in other, more complex, cereals such as wheat. Expected outcomes will be fundamental breakthroughs in understanding how plants respond to, and buffer, the effects of heat to lead to translational breeding strategies that bolster grain yield.Read moreRead less
ARC Centre of Excellence in Plant Cell Wall Biology. The ARC Centre for Plant Cell Wall Biology will define the regulatory mechanisms that control molecular, enzymic and cellular processes involved in the synthesis, deposition, re-modelling and depolymerisation of cell wall polysaccharides of cereals and grasses. Plant cell walls represent the world's largest renewable carbon resource, but the regulatory mechanisms responsible for their synthesis and assembly are not understood. Key distinguishi ....ARC Centre of Excellence in Plant Cell Wall Biology. The ARC Centre for Plant Cell Wall Biology will define the regulatory mechanisms that control molecular, enzymic and cellular processes involved in the synthesis, deposition, re-modelling and depolymerisation of cell wall polysaccharides of cereals and grasses. Plant cell walls represent the world's largest renewable carbon resource, but the regulatory mechanisms responsible for their synthesis and assembly are not understood. Key distinguishing features of the Centre will be the international, integrative, and multidisciplinary approach towards addressing major questions in plant biology, its strategy to leverage ARC funding, and its linkages with potential national and international end-users of the fundamental scientific discoveries.Read moreRead less
Australian Laureate Fellowships - Grant ID: FL180100139
Funder
Australian Research Council
Funding Amount
$2,973,547.00
Summary
Processes of plant growth that impact agriculture and horticulture. The project aims to discover the genes and processes that control plant shoot architecture, which is a major driver of yield in field, horticultural and forestry crops. Shoot branching is the result of the complex interplay of genes, environment and crop management. By investigating cellular processes governing growth and development, as well as physiology and molecular genetics, this project will enhance Australian capacity and ....Processes of plant growth that impact agriculture and horticulture. The project aims to discover the genes and processes that control plant shoot architecture, which is a major driver of yield in field, horticultural and forestry crops. Shoot branching is the result of the complex interplay of genes, environment and crop management. By investigating cellular processes governing growth and development, as well as physiology and molecular genetics, this project will enhance Australian capacity and multidisciplinary innovation. An improved understanding of shoot branching and how it may be manipulated will improve our knowledge of plant sciences that could contribute to agricultural expansion and food security in Australia and internationally.Read moreRead less
Discovering the activity of novel CLE peptide hormones that regulate legume nodulation. This project aims to functionally characterise novel peptide hormones that regulate the number of nitrogen-fixing root nodules that legumes form. Findings will enhance the current nodulation model and could help to alleviate our reliance on expensive, often polluting, nitrogen-fertilisers by helping to optimise the nodulation process in agriculture.
Discovery of the systemic regulator of legume nodulation. This project aims to discover the novel, shoot-derived factor that legumes produce to regulate the number of nitrogen-fixing root nodules they form. Outcomes will enhance the current nodulation model and could help optimise the process in agriculture, which would help alleviate current reliance on nitrogen-fertilisers that are expensive and pollute.
Monolayer crystallization of membrane proteins. Membrane proteins comprise 25-40% of all proteins and conduct a myriad of finely tuned reactions in every cell. Despite their importance and diversity only ~40 membrane protein structures have been solved, due to the difficulty of producing high quality 2D and 3D crystals. We propose to develop and use the new monolayer crystallization technique, which employs a lipid monolayer as a crystallization template for 2D crystal production. A number of ....Monolayer crystallization of membrane proteins. Membrane proteins comprise 25-40% of all proteins and conduct a myriad of finely tuned reactions in every cell. Despite their importance and diversity only ~40 membrane protein structures have been solved, due to the difficulty of producing high quality 2D and 3D crystals. We propose to develop and use the new monolayer crystallization technique, which employs a lipid monolayer as a crystallization template for 2D crystal production. A number of important membrane proteins are available for these structural studies including ABC transporters, Caveolin-3 and the NS1 protein of Dengue virus, all of which are difficult to crystallize using conventional techniques.Read moreRead less