A Novel Cytokine-receptor Survival Axis In Chronic Myeloid Leukaemia
Funder
National Health and Medical Research Council
Funding Amount
$424,731.00
Summary
Cancer cells grow and survive in an unrestrained manner. Current therapies target cancer growth, however they permit the long-term survival of some cancer cells and increase the possibility of drug resistance and disease relapse. We have identified a new molecular switch that is constitutively activated (unregulated) in leukemia. Targeting specific components of this unregulated cell survival may provide new and improved approaches for the development of therapeutics in the treatment of leukemia
Structural Studies On Cell Signalling Via The LIF Receptor And Gp130
Funder
National Health and Medical Research Council
Funding Amount
$453,943.00
Summary
The cytokines play important roles in the immune system during blood cell development and inflammation, and in nerve growth, bone remodeling, reproduction and heart development. Cell responses are initiated by a cytokine bringing together on the cell surface a receptor complex made up of multiple molecules. This project will investigate the atomic structure of the cell surface macromolecular complex, and hence the underlying mechanism by which cytokine signals are initiated.
Role Of Conformational Change In Activation Of The Growth Hormone Receptor
Funder
National Health and Medical Research Council
Funding Amount
$242,545.00
Summary
Growth hormone is an important hormone therapeutic for treating dwarfism. Recently, many new therapeutic applications for growth hormone have been discovered, particularly in relation to its role as an anabolic agent. These include post surgery recovery, enhanced bone fracture healing, Crohns disease, dilated cardiomyopathy, infertility and of course, ageing. This project seeks to find out how growth hormone sends its signal into the target cell through its surface receptor. It is believed that ....Growth hormone is an important hormone therapeutic for treating dwarfism. Recently, many new therapeutic applications for growth hormone have been discovered, particularly in relation to its role as an anabolic agent. These include post surgery recovery, enhanced bone fracture healing, Crohns disease, dilated cardiomyopathy, infertility and of course, ageing. This project seeks to find out how growth hormone sends its signal into the target cell through its surface receptor. It is believed that the primary event in signalling is the ability of the hormone to bring two receptors together (receptor dimerization). However, it may be that the receptor already is dimerized, and the role of the hormone is to induce a specific change in shape of the receptor, which transfers the signal of hormone binding into the cell to initiate signalling to the genome. We have good evidence that a specific shape change is required for activation of an important signalling pathway by growth hormone, and the closely structurally related receptor for erythropoietin is already dimerized before hormone binds. We want to find out exactly how the shape change acts, and whether the receptor is predimerized. This information is vital for designing small orally active mimics of growth hormone which could be of great value as an anabolic supplement for the frail elderly.Read moreRead less
The Structural Basis Of Cytokine Signalling Inhibition
Funder
National Health and Medical Research Council
Funding Amount
$239,473.00
Summary
Cell-cell communcation is vital for the correct functioning of the body. Cells need to be told the correct time to divide, to produce certain enzymes or chemicals, to migrate and also when to apoptose, or die. Cells receive these signals through the binding of small soluble proteins called cytokines. Cytokines bind to specialized receptors on the surface of the cell and initiate an intracellular signaling cascade that passes the correct message to the nucleus. It is important that cells react to ....Cell-cell communcation is vital for the correct functioning of the body. Cells need to be told the correct time to divide, to produce certain enzymes or chemicals, to migrate and also when to apoptose, or die. Cells receive these signals through the binding of small soluble proteins called cytokines. Cytokines bind to specialized receptors on the surface of the cell and initiate an intracellular signaling cascade that passes the correct message to the nucleus. It is important that cells react to these protein messengers however it is just as vital that they don't overreact. Many human diseases, especially inflammatory diseases such as rheumatoid arthritis and type II diabetes, are due to aberrant cytokine signaling. To ensure this doesn't occur, cells have evolved a mechanism to quickly switch off the signaling cascade after it has started. This mechanism involves an entire family of proteins, the Suppressors of Cytokine Signalling (SOCS) family. These proteins can act via two distinct mechanisms. The first is to directly block the JAK-STAT proteins, proteins that initiate the intracellular part of the signaling cascade. The second mechanism has been less well studied, it involves the SOCS proteins upregulating the degradation of signaling intermediates. The SOCS proteins can do this through the action of a 40 residue domain called the SOCS box. The SOCS box directs proteins bound to other domains of the SOCS proteins to be degraded by interacting with a complex called an E3 ubiquitin ligase. This project involves determining the three-dimensional atomic structure of the SOCS-E3 ligase interaction and investigating biophysical aspects of the interaction. This information will lead to a fuller understanding of the mechanism of signaling inhibition and will provide information crucial to the design of SOCS inhibitors. Such inhibitors would be therapeutically important in the treatment of a number of human diseases such as cancer, arthritis and type II diabetes.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.
Cytokine Secretion: A Model For Protein Trafficking.
Funder
National Health and Medical Research Council
Funding Amount
$204,111.00
Summary
TNF-a is an inflammatory cytokine with important roles in host defense, tumour regulation and energy homeostatis, however the oversecretion of TNF-a is also a major cause of septic shock, rheumatoid arthritis, Chron?s disease and the cachexia of cancer. TNF-a synthesis and its release from the surface of cells are relatively well understood. However little is known about its trafficking through the secretory pathway of cells. Understanding this process has the potential to provide new ways of co ....TNF-a is an inflammatory cytokine with important roles in host defense, tumour regulation and energy homeostatis, however the oversecretion of TNF-a is also a major cause of septic shock, rheumatoid arthritis, Chron?s disease and the cachexia of cancer. TNF-a synthesis and its release from the surface of cells are relatively well understood. However little is known about its trafficking through the secretory pathway of cells. Understanding this process has the potential to provide new ways of controlling the secretion of TNF-a. In previous work we have characterized transport vesicles and cytoskeletal proteins involved in secretory pathways of epithelial cells. We now propose to focus on the characterization of transport vesicles, and the roles of actin and myosins involved in TNF-a secretion in macrophages. These studies will rely on introducing new technology to this line of research. Fluorescent tagged constructs of TNF-a will be expressed and viewed in living cells to analyse the secretory pathway and measure the transport of TNF-a from its site of accumulation in the Golgi complex to the cell surface. This work aims to identify membrane-bound vesicles and vesicle-associated proteins that target TNF-a for secretion. We will begin to investigate the role of actin and myosins, using drugs and microinjected peptides to block their function. Overall these studies will provide important cell biological information about protein trafficking in cells. Cytokine secretion is important in immunity and cancer, information important to both fields will be gained from these studies.Read moreRead less