The regulated movement of membrane receptors and ligands between the cell surface and intracellular compartments is vital to many cellular operations, including communication between cells and their environment. However, the molecular details of these sorting events remain poorly defined. Determination of the mechanisms that control the cellular distribution of receptors is critical for understanding normal cellular processes and in pathological processes like tumorigenesis.
Role Of PAK1 In Colorectal Cancer Growth And Metastasis Regulated By Gastrins
Funder
National Health and Medical Research Council
Funding Amount
$460,070.00
Summary
Increased level of PAK1(a protein kinase) was associated with the progression of colorectal (large bowel) cancer (CRC). Gastrin peptides are growth factors responsible for CRC development. The objective of this project is to determine the role of PAK1 in the regulation of CRC growth and metastasis by gastrin peptides. We will use cell culture, animal models and clinical samples in the program. A successful outcome will lead to the development of new CRC therapies such as inhibitors of PAK1.
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.
Fluorescence Analysis Of The EGFreceptor Signalling Network
Funder
National Health and Medical Research Council
Funding Amount
$490,750.00
Summary
Receptors are cell-surface molecules that enable the cell to receive chemical messages from the outside environment and transmit these signals to the inside of cell. These messages tell the cells to grow, divide or die. The Epidermal Growth Factor Receptor is linked to a variety of cell signalling pathways that are critical to the normal functioning of cells. Conversely, abberations in Epidermal Growth Factor-mediated cell signalling leads to many types of cancers. A basic understanding of how t ....Receptors are cell-surface molecules that enable the cell to receive chemical messages from the outside environment and transmit these signals to the inside of cell. These messages tell the cells to grow, divide or die. The Epidermal Growth Factor Receptor is linked to a variety of cell signalling pathways that are critical to the normal functioning of cells. Conversely, abberations in Epidermal Growth Factor-mediated cell signalling leads to many types of cancers. A basic understanding of how the receptor is turned off or on is essential to designing drugs that can specifically inhibit its hyperproliferative response. High resolution structures of a key part of the Epidermal Growth Factor Receptor have identified several structural forms of the receptor that are providing valuable clues as to the structural basis for receptor activation. Armed with this information and advanced microscopic imaging technology we are in the unique position to probe receptor activation in living cells. This project seeks to determine which structural form of the receptor is responsible for transmission of cellular messages and how it is impaired in cancerous cells.Read moreRead less
Investigating The Physiological And Biochemical Role Of SOCS5 In The Immune System
Funder
National Health and Medical Research Council
Funding Amount
$405,940.00
Summary
Asthma affects millions of people worldwide and is a complex inflammatory disease of the lung. Asthma manifests as recurrent episodes of wheezing, breathlessness, chest tightening, and coughing. Three key proteins called; interleukin 4 (IL-4), interleukin 13 (IL-13) and interleukin 5 (IL-5) are produced by a subset of white blood cells (T helper cells; Th2) and are thought to be responsible for the asthma response. Normally these proteins act to coordinate the body s immune defence against paras ....Asthma affects millions of people worldwide and is a complex inflammatory disease of the lung. Asthma manifests as recurrent episodes of wheezing, breathlessness, chest tightening, and coughing. Three key proteins called; interleukin 4 (IL-4), interleukin 13 (IL-13) and interleukin 5 (IL-5) are produced by a subset of white blood cells (T helper cells; Th2) and are thought to be responsible for the asthma response. Normally these proteins act to coordinate the body s immune defence against parasite infection. In other words, asthma is thought to arise through inappropriate IL-4 and IL-13 activity in the absence of a parasite infection. Extra IL-13 is commonly found in the lungs of asthmatics and is thought to help trigger asthma attacks. IL-13 is a validated target for drugs that could be used in the treatment of asthma. The SOCS genes were discovered in our laboratory and by genetically deleting the genes in mice we have demonstrated a critical role for SOCS1, SOCS2 and SOCS3 in regulating the immune response and the action of growth hormone. My hypothesis is that SOCS5 is an important physiologic regulator of the asthma response. This proposal will investigate the basic biochemical processes underlying the regulation of IL-4 and IL-13 action and the relationship to development of asthma and immune disease. I plan to induce asthma attacks in mice that lack the genes for SOCS4 and SOCS5. If the severity of the attacks is greater in the absence of these proteins this will indicate that SOCS4 and-or SOCS5 are important negative regulators of IL-4 and IL-13. This has the potential to open up a completely new strategy for the development of drugs that could be used in the prevention and treatment of asthma.Read moreRead less
Tumour cells are often characterized by defects in signaling pathways. One of the most important signaling cascades involved in the development of cancer is the EGFR-Ras-MAPK pathway. EGFR is often overexpressed in breast cancer, leading to enhanced Ras signaling (hyperactive Ras) and cell transformation. The proposed project aims to identify the molecular mechanisms that can downregulate hyperactive Ras and will make a valuable contribution to our understanding of EGFR-Ras related cancers.
This established team of investigators will research into the molecular control of white blood cell formation and function, using a multidisciplinary, team approach to fundamental biological questions with a focus on potential clinical and commercial outcomes. The team will also attempt to identify new validated targets for therapeutic intervention by using both forward and reverse genetic approaches in mice coupled with complete phenotypic analyses of the blood cell system.
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
Regulation Of Body Composition And Glucose Homeostasis By The Adaptor Protein Grb10.
Funder
National Health and Medical Research Council
Funding Amount
$617,256.00
Summary
Resistance to the hormone insulin underlies the development of Type 2 Diabetes. Loss of muscle mass in the elderly contributes to insulin resistance. Recently we identified Grb10 as a new regulator of insulin action and muscle mass. In this proposal, we aim to study how Grb10 affects development and growth of muscle and fat, and the underlying molecular mechanisms. This may lead to new strategies for improving body composition and treating the insulin resistance associated with Type 2 Diabetes.