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
A TriaL Assessing N-3 As Treatment For Injury-induced Cachexia (ATLANTIC Trial)
Funder
National Health and Medical Research Council
Funding Amount
$480,245.00
Summary
The anti-inflammatory properties of fish oil are well documented. Hip fracture is common and patients suffer significant inflammation, unintentional weight and muscle loss leading to poor outcomes. This study aims to reduce the weight loss suffered by hip fracture patients by prescribing an intervention of individualised nutrition support and high dose fish oil.
Defining Mechanisms Of Follistatin-mediated Muscle Adaptation, For Treatment Of Frailty And Muscle-related Diseases
Funder
National Health and Medical Research Council
Funding Amount
$557,478.00
Summary
Physical frailty-weakness is one of the most common symptoms of serious illness and a key cause of death. I propose to study a new model of skeletal muscle growth, to learn more about the causes of wasting in muscle-related diseases. The work will identify cell mechanisms that cause loss of muscle strength, and will help develop novel treatment approaches to prevent or reverse physical frailty in illness. New therapies to combat frailty are vital to improve the health of our community.
The Mechansim Of Cachexia Induced By The TGF-b Superfamily Cytokine, MIC-1
Funder
National Health and Medical Research Council
Funding Amount
$544,200.00
Summary
MIC-1 is a protein first cloned and characterised by our research group. It belongs to the TGF beta protein superfamily which is very important in development of cancer, wound - fracture healing and inflammation. Recent evidence also suggests it can act as an appetite suppressant, and this is especially relevant in conditons like cancer where it is overproduced. This project seeks to understand the mechanisms for its capacity to modify appetite
Development Of A Specific Activin Antagonist For Therapeutic Applications
Funder
National Health and Medical Research Council
Funding Amount
$504,287.00
Summary
Activin is a key regulator of homeostasis in several organs and tissues, including ovaries, testes, liver and skin, and alterations in activin�s activity can result in fibrosis, cachexia and cancer. In this grant we propose to develop a specific activin antagonist by modifying the activin A propeptide. This novel reagent could be used to promote liver growth in severe hepatic disease and prevent fibrosis in numerous tissues.
MicroRNA Dysregulation As A Mechanism Underlying Muscle Wasting
Funder
National Health and Medical Research Council
Funding Amount
$514,454.00
Summary
Frailty caused by muscle wasting shortens many peoples' lives and costs hundreds of billions of dollars in care and lost productivity annually. In the hope of finding ways to treat frailty, we will study whether naturally-occurring microRNA molecules are responsible for disrupting gene expression to cause muscle disease. We will identify which types of microRNA are altered in muscle diseases, and test whether adjusting microRNA levels with new approaches can prevent-treat muscle wasting.
Role Of Betaglycan In Gonadal And Adrenal Tumourigenesis
Funder
National Health and Medical Research Council
Funding Amount
$487,500.00
Summary
TGF-beta and inhibin are related multifunctional growth factors which regulate a number of important cellular functions, including proliferation, differentiation, and survival. Betaglycan is a cell-surface protein that binds both inhibin and TGF-beta. Betaglycan appears to regulate the binding and availability of the TGF-betas and inhibins to their signaling receptors, and its presence on the cell surface increases the efficiency of TGF-beta and inhibin function. Deletion of the inhibin gene in ....TGF-beta and inhibin are related multifunctional growth factors which regulate a number of important cellular functions, including proliferation, differentiation, and survival. Betaglycan is a cell-surface protein that binds both inhibin and TGF-beta. Betaglycan appears to regulate the binding and availability of the TGF-betas and inhibins to their signaling receptors, and its presence on the cell surface increases the efficiency of TGF-beta and inhibin function. Deletion of the inhibin gene in mice produces tumours in the ovary, testis, and adrenal gland in 100% of the mice. In this current proposal, we will delete the betaglycan gene in the primary target tissues for inhibin (the anterior pituitary and gonads). The hypothesis we are testing is that the loss of a co-receptor for inhibin (i.e. betaglycan) results in a loss of cellular sensitivity to inhibin, thus resulting in altered growth characteristics which predispose the gonads and adrenals to cancer. We will examine these cells in culture and in living animals to determine whether our hypotheses are correct. We will also conduct a series of histological, biochemical, and biological experiments in order determine the underlying causes of any observed growth dysregulation. This work is expected to yield information relevant to the role of betaglycan in inhibin-TGFb-regulated processes in normal and cancerous growth, which may allow future design of therapies for cancer.Read moreRead less
The Nature And Significance Of Clonal Evolution In Human Melanoma
Funder
National Health and Medical Research Council
Funding Amount
$665,420.00
Summary
Cancers can progress in patients by developing genetic changes that favor the growth, survival and spread of cancer cells. However, the rate at which genetic changes occur in human cancer is not known. This project will determine the degree and biological significance of genetic change in human melanoma by using a novel method of growing tumors from single cells and comparing genetic differences between them.
Identifying The Targets Of MiRNA Regulation In Cancer
Funder
National Health and Medical Research Council
Funding Amount
$290,600.00
Summary
microRNAs are noncoding RNAs with fundamental functions in biology and significant roles disease. microRNAs control gene expression by destroying RNA or controlling its translation into cellular proteins. To determine how certain microRNAs cause human disease it is essential to know their RNA targets. We are developing methods to identify these targets and aim to apply these methods to identify the targets of microRNAs with known roles in cancer.
Polycomb Group Genes In Murine Lymphomagenesisand Their Impact On Drug Response.
Funder
National Health and Medical Research Council
Funding Amount
$476,815.00
Summary
The success of lymphoma treatment with current drugs is limited by drug resistance. Some crucial links between genes which cause cancer and genes which alter response to cancer treatment have been identified: the cellular machinery that cancer cells use to become cancer cells in the first place, is often the same machinery that cancer cells later use to become resistant to cancer treatments. The Polycomb Group family controls expression of other critical genes: that is, they dictate which genes ....The success of lymphoma treatment with current drugs is limited by drug resistance. Some crucial links between genes which cause cancer and genes which alter response to cancer treatment have been identified: the cellular machinery that cancer cells use to become cancer cells in the first place, is often the same machinery that cancer cells later use to become resistant to cancer treatments. The Polycomb Group family controls expression of other critical genes: that is, they dictate which genes are switched on, where, and when. This determines whether a cell behaves normally or whether it may turn into a cancer cell. When Polycomb Group genes themselves are expressed at the wrong time or place, they can cause cancer. In human lymphoma, these genes have been associated with more aggressive lymphoma. This has also been shown for other cancers such as breast and prostate cancer. In some cases these genes are associated with cancers that do worse following anti-cancer treatment. So far, no research has been published looking the direct impact of the Polycomb Group genes on the success of treatment in a controlled laboratory model. We have used a powerful laboratory mouse model of lymphoma, established in the host laboratory, in which over-expression of the c-myc oncogene in developing B cells causes lymphoma. This model is easy to manipulate and this provides us with a great deal of experimental control, much more than can be achieved from working with patient samples. Two family members, Bmi-1 and Cbx7, cause lymphoma to develop aggressively and we will ask whether two other members, Ezh2 and Rybp do this as well. We will determine whether these 4 genes cause drug resistance in lymphoma, with currently used chemotherapy and also with novel anti-cancer drugs. By increasing our understanding of drug resistance in lymphoma, drugs may be utilised more effectively and new markers identified to predict which drug will be successful in treating a particular lymphoma.Read moreRead less