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.
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.
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
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
Physiological Significance Of Cellular Translocation Of The Intestine-specific Homeodomain Protein Cdx2
Funder
National Health and Medical Research Council
Funding Amount
$196,527.00
Summary
Ulcerative colitis and Crohn's disease are debilitating inflammatory diseases of the bowel. Conservative estimates (Australian Crohn's and Colitis Association) suggest that at least 23,000 Australians are affected (>1 in 1000). Ten years after onset, there is an estimated risk of 0.5-1.0% per year of pancolitis patients developing full-blown bowel cancer. Current therapies for colon cancer are not very effective and the median survival for patients with metastatic disease is poor at 7-12 mont ....Ulcerative colitis and Crohn's disease are debilitating inflammatory diseases of the bowel. Conservative estimates (Australian Crohn's and Colitis Association) suggest that at least 23,000 Australians are affected (>1 in 1000). Ten years after onset, there is an estimated risk of 0.5-1.0% per year of pancolitis patients developing full-blown bowel cancer. Current therapies for colon cancer are not very effective and the median survival for patients with metastatic disease is poor at 7-12 months. It is therefore important to increase our understanding of the biology underlying these inflammatory conditions so that more effective treatments may be developed and fewer patients proceed to the cancerous stage. We have recently demonstrated a novel interaction between two proteins that may be relevant to intestinal inflammation. Surprisingly, the two proteins would not normally be expected to coincide with each other because of their different localisations within cells and tissues. The first protein, Cdx2, is only synthesised by intestinal lining cells and normally resides in the nucleus where it activates genes that play a role in the highly specialised absorptive functions of the intestine. The other protein, acrogranin-granulin, is more widely distributed in the body and is generally transported out of cells shortly after it has been made. It has been shown to interact with receptors on epithelial cells and blood cells and promotes their growth. In this proposal we will be investigating whether the complex formed between Cdx2 and granulin is important for normal physiology. Moreover since elevated levels of granulin are associated with inflammation, we aim to determine whether the Cdx2-granulin complex is formed during the active phase of ulcerative colitis and Crohn's disease. Specifically, we will test the hypothesis that the Cdx2-granulin complex plays an important role in repairing the damage caused to the lining of the intestine during inflammation.Read moreRead less
Post-genomic investigation of the relict plastid and mitochondrion of malaria parasites. Malaria is a major global health problem. The malaria parasite has two substructures, a relict chloroplast and a mitochondrion, that are excellent targets for new and existing drugs. However, we do not know the key functions of these two compartments. The entire genetic blueprint (genome) is now available for the malaria parasite and I propose to determine exactly which parts of the genome service the rel ....Post-genomic investigation of the relict plastid and mitochondrion of malaria parasites. Malaria is a major global health problem. The malaria parasite has two substructures, a relict chloroplast and a mitochondrion, that are excellent targets for new and existing drugs. However, we do not know the key functions of these two compartments. The entire genetic blueprint (genome) is now available for the malaria parasite and I propose to determine exactly which parts of the genome service the relict chloroplast and mitochondria. This will sketch out a picture of their inner workings. Armed with this information we can take a rational approach to seeking an Achilles? Heel of malaria against which parasite-specific drugs can be developed.Read moreRead less
Functional Characterisation Of N4WBP5 And N4WBP5A, Novel Nedd4-interacting Proteins
Funder
National Health and Medical Research Council
Funding Amount
$480,750.00
Summary
The proteins that make up a cell must be correctly localised in order to perform their normal function. Specialised cellular activities are carried out in distinct compartments within a cell and proteins must correctly localise in them and traffic between them. Intracellular protein trafficking is a highly regulated process involving many components. Recent findings have shown that intracellular trafficking is regulated in many cases by distinct protein modifications. One such modification is ta ....The proteins that make up a cell must be correctly localised in order to perform their normal function. Specialised cellular activities are carried out in distinct compartments within a cell and proteins must correctly localise in them and traffic between them. Intracellular protein trafficking is a highly regulated process involving many components. Recent findings have shown that intracellular trafficking is regulated in many cases by distinct protein modifications. One such modification is tagging of a small protein called ubiquitin to proteins that are being trafficked. A focus of research in our laboratory is the study of a protein, called Nedd4, which directly tags proteins with ubiquitin. We have recently identified two novel proteins that interact with Nedd4 and localise to distinct subcellular compartments that are sites for the correct sorting and delivery of proteins trafficking within the cell. The main aim of our proposal is to characterise how these proteins function. We propose that these proteins are involved in intracellular trafficking and that they may function by targeting Nedd4 to the cellular trafficking machinery. This may be required for Nedd4 to tag molecules with ubiquitin that are involved in intracellular trafficking. Our experiments will test the functional relationship between Nedd4 and the novel proteins and determine the particular trafficking pathways in which these proteins are involved. Defects in cellular processes regulated by Nedd4 and other similar proteins cause a number of human diseases including an inherited form of hypertension and a specific group of cancers. In addition, a large number of human diseases result directly from defects which disrupt intracellular trafficking pathways. The results of this study will provide further insight into this essential cellular process and may ultimately contribute to the development of therapies for diseases resulting from defects in intracellular trafficking.Read moreRead less
Approaches to combat AIDS and its causative agent, the human immunodeficiency virus HIV-1, have thus far proved ineffective. The proposed research program intends to investigate the nuclear import of two HIV-1 proteins which have central roles in HIV infection. We will apply our expertise in the area of the regulation of nuclear import of viral proteins, and build on our observations with respect to these proteins to attempt to establish the mechanistic basis of their nuclear import, and how thi ....Approaches to combat AIDS and its causative agent, the human immunodeficiency virus HIV-1, have thus far proved ineffective. The proposed research program intends to investigate the nuclear import of two HIV-1 proteins which have central roles in HIV infection. We will apply our expertise in the area of the regulation of nuclear import of viral proteins, and build on our observations with respect to these proteins to attempt to establish the mechanistic basis of their nuclear import, and how this differs from the conventional nuclear import pathways used by normal cellular proteins. We already have evidence that nuclear import of HIV-Tat is regulated in novel fashion by cellular factors, and intend, through determining its mechanistic basis, to be able to form the basis of a strategy to block this import pathway specifically, and thereby inhibit HIV replication. This may form the basis in the future of a new pharmaceutical approach to combat HIV-AIDS.Read moreRead less