Defining The Mechanism Of Assembly Of Herpes Simplex Virus In The Neuronal Growth Cone And Its Subsequent Exit To Epithelial Cells
Funder
National Health and Medical Research Council
Funding Amount
$774,624.00
Summary
Herpes simplex virus (HSV) causes dormant infection of nerve cell bodies near the spine. It periodically reactivates to be transported along nerves to the skin where it causes oral, genital or neonatal herpes and mediates HIV superinfection. HSV assembles into its final form in the terminal part of the axon just prior to crossing into skin. Elucidating the mechanism of HSV assembly and exit will facilitate new strategies for antiviral agents and immune treatment for HSV and similar viruses.
Using A Novel Gut Culture System To Analyse The Influence Of Genes Mutated In Colon Cancer On Epithelial Cell Growth
Funder
National Health and Medical Research Council
Funding Amount
$436,650.00
Summary
Colorectal (or bowel) cancer is a major health problem in Australia. Approximately 1 in 21 Australians will develop the disease in his-her lifetime. The risk of bowel cancer increases with age, with the risk rising progressively and sharply from the age of 50. Current therapies for colorectal cancer are not very effective and the median survival for patients with this disease is poor at 7- 12 months. The development of colorectal cancer is complex and is affected by both genetic and environmenta ....Colorectal (or bowel) cancer is a major health problem in Australia. Approximately 1 in 21 Australians will develop the disease in his-her lifetime. The risk of bowel cancer increases with age, with the risk rising progressively and sharply from the age of 50. Current therapies for colorectal cancer are not very effective and the median survival for patients with this disease is poor at 7- 12 months. The development of colorectal cancer is complex and is affected by both genetic and environmental factors. Colorectal cancer progresses through a number of distinct pathological stages. This is thought to be the result of the progressive aquisition of mutations in genes that normally ensure a balance between cell growth and cell death. Mutations in a number of genes (known as APC, K-ras, p53, SMAD2, SMAD4) are commonly found in colorectal tumours. This research is aimed at understanding how genes which are altered in colon cancer influence the growth of cells in normal intestine. We have developed a system where normal mouse gut can be maintained and grown intact. Genes containing the alterations found in colon cancer will be introduced into the normal gut epithelial cells and the effects on the growth and behaviour of these cells analysed. This should improve our knowledge of how these altered genes contribute to the development of colon cancer.Read moreRead less
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
Differentiation Of Pro-fibrotic From Anti-inflammatory Effects Of TGF-? In Kidney Fibrosis By Targeting ?-catenin
Funder
National Health and Medical Research Council
Funding Amount
$593,019.00
Summary
More than 2500 Australians commence kidney replacement therapy each year and many more die of kidney failure as a result of kidney fibrosis. TGF-?, a growth factor causing kidney fibrosis, is also anti-inflammatory. Our project aims to prove that targeting a downstream messenger (?-catenin) of TGF-? will prevent kidney fibrosis while leaving TGF-?’s anti-inflammatory actions untouched. A successful outcome will lead to a novel cure for preventing kidney fibrosis and fibrosis of other organs.
This work will analyse how cells, the building blocks of tissues, are organized together to form functioning organs. It focuses on the adhesion molecules that allow cells to recognize one another, which cooperate with the internal skeleton of cells to link them together. We aim to understand how these cellular systems work normally and how they are targeted to disrupt tissue integrity in diseases like cancer and inflammation.
Our current understanding of cellular signalling and disease is based on ensemble measurements over a cellular or molecular population. While these measurements have provided valuable information on the molecular circuitry required for cellular function, there is a lack of detail on the spatio-temporal dynamics of signal initiation and propagation at the single molecule and single cellular level. Single particle (molecule or cell) approaches offer the advantage of being able to detect individual ....Our current understanding of cellular signalling and disease is based on ensemble measurements over a cellular or molecular population. While these measurements have provided valuable information on the molecular circuitry required for cellular function, there is a lack of detail on the spatio-temporal dynamics of signal initiation and propagation at the single molecule and single cellular level. Single particle (molecule or cell) approaches offer the advantage of being able to detect individual processes including rare events that would be lost in an ensemble measurement. Moreover single particle approaches provide dynamic-kinetic information that does not rely on synchronising a population of molecules or cells. In this proposal we aim to build on our combined expertise in EGF-EGFR signalling, biophysics, biosensors, quantum dot nanotechnology and single molecule spectroscopy to learn more about how EGFR cellular signalling works and how it is impaired in cancer. This project will provide basic information that could lead to the design of more effective drugs directed agaisnt this therapeutic target.Read moreRead less