Control Of The Ras/Erk Signaling Pathway By The Brahma Chromatin-remodeling Complex
Funder
National Health and Medical Research Council
Funding Amount
$524,820.00
Summary
Hormones bind and initiate molecular signals within cells to proliferate or change into specific cell types. This is important for growth and development of different tissues. A pathway which is critical for transmitting the effects of hormones in cells is the Ras pathway. New studies by the applicants indicate that the Brahma complex, a molecule important in controlling the levels of proteins in cells, activates the Ras pathway. This project will define how Brahma controls the Ras pathway.
Breast cancer is the most frequent malignancy among women, with an estimated 1 million new cases per year worldwide. A family of enzymes known as protein tyrosine kinases (PTKs) are fundamental in the initiation and progression of tumour growth and they are frequently hyperactivated in breast cancer. This proposal will examine whether inactivation of the enzyme known as TCPTP contributes to PTK hyperactivation and tumorigenicity in breast cancer.
Altered Gp130-mediated Signalling In The Regulation Of Pulmonary Fibrosis
Funder
National Health and Medical Research Council
Funding Amount
$373,956.00
Summary
Pulmonary fibrosis is a chronic diffuse interstitial lung disease often of unknown cause, characterised pathologically by inflammation and fibrosis of the lung tissue. The prognosis is poor with a 50% mortality at five years after diagnosis and considerable morbidity during those years. Previous investigations have documented the role for inflammation in the development of pulmonary fibrosis and current therapeutic strategies are aimed at suppressing the inflammation using anti- inflammatory dru ....Pulmonary fibrosis is a chronic diffuse interstitial lung disease often of unknown cause, characterised pathologically by inflammation and fibrosis of the lung tissue. The prognosis is poor with a 50% mortality at five years after diagnosis and considerable morbidity during those years. Previous investigations have documented the role for inflammation in the development of pulmonary fibrosis and current therapeutic strategies are aimed at suppressing the inflammation using anti- inflammatory drugs, almost exclusively steroids. The effectiveness of steroids is variable although generally poor and can be associated with significant side effects suggesting that other approaches need to be considered. Data generated over the past decade also have established the concept that the molecular processes underlying the development of fibrosis may represent a new opportunity for therapeutic intervention. This project will build on previous studies examining the effects of a family of molecules called cytokines that signal through gp130 as critical determinants of disease susceptibility and progression. gp 130 is a shared component in the receptor complexes for IL-6 family cytokines and can signal down two major pathways. We have shown that the development of lung fibrosis depends on which specific signalling pathway is used. This study will determine how fibrosis is controlled by these pathways. Our data raises the possibility of developing pharmacological manipulators of gp130 signalling pathways that would suppress fibrosis but leave normal cellular defense mechanisms necessary for host defense in the lung intact.Read moreRead less
Characterisation Of Notch Asparaginyl Hydroxylation By FIH-1.
Funder
National Health and Medical Research Council
Funding Amount
$307,841.00
Summary
Cells within our body receive numerous signals telling them when to grow, when to turn into another cell type and exactly what type, and even how to respond to situations like low oxygen. These signals and cells response are very important during embryonic development, when these signals cause a single cell to become a complete person, and also in adults. Here in the embryo, and also in adults, stem cells are very important because they can become many different kinds of cells, depending on what ....Cells within our body receive numerous signals telling them when to grow, when to turn into another cell type and exactly what type, and even how to respond to situations like low oxygen. These signals and cells response are very important during embryonic development, when these signals cause a single cell to become a complete person, and also in adults. Here in the embryo, and also in adults, stem cells are very important because they can become many different kinds of cells, depending on what the body needs. When the signals don't work properly, they cause major problems and diseases, from birth defects, to cancer. Notch is an important protein involved in receiving and passing on certain signals, and is found in organisms as diverse as worms and humans. It tells cells, especially stem cells and other similar cells, when and how to change from one type of cell to another. For example, it is very important in the generation of many different types of blood cells from a single precursor cell. Notch has also been implicated in human diseases such as cancer, where signalling goes wrong and cells keep multiplying out of control, and also certain types of heart disease. Another protein, called FIH, is an oxygen sensor that signals to the cell when there is not enough oxygen around. FIH has also been implicated in cancer and heart disease. We have recently found evidence suggesting that FIH can also influence the activity of the Notch proteins. This means that oxygen levels can potentially have an effect on stem cells and other processes controlled by Notch, and may be very important in cancer and other diseases. This project will first confirm the connection between FIH and Notch. There are a number of different Notch proteins, so we will see if this connection works with all of them. It will also try and work out the consequence of this connection is and how important it is. Finally, the likely biological consequences on human diseases, specifically cancer.Read moreRead less
The Role Of SKAM And Sphingosine Kinase In Wound Healing
Funder
National Health and Medical Research Council
Funding Amount
$281,340.00
Summary
Many aspects of wound healing are poorly understood. We have identified a novel cellular pathway that appears critically involved in controlling wound contraction. This project aims to characterise this cellular pathway to understand the exact mechanisms whereby it controls this critical aspect of wound healing. With this information we will develop topical therapeutics to aid the wound healing process.
Regulation Of Insulin Sensitivity By Reactive Oxygen Species
Funder
National Health and Medical Research Council
Funding Amount
$564,644.00
Summary
In morbid obesity and type 2 diabetes chronic levels of reactive oxygen species (ROS) are detrimental and diminish insulin's ability to maintain normal blood glucose levels. Paradoxically, ROS also promote insulin action by inhibiting enzymes known as protein tyrosine phosphatases (PTPs). This proposal will determine whether the promotion of ROS for the inhibition of PTPs early in the progression of type 2 diabetes may be of therapeutic benefit.
Receptor Signalling Through Intracellular Calcium Stores In Chromaffin Cells
Funder
National Health and Medical Research Council
Funding Amount
$461,000.00
Summary
The function of cells in the body is controlled by many hormones and neurotransmitters acting on the cell's surface. Hormones and transmitters mediate their effects by producing chemical signals within the cell that regulate its activities. One key cell signalling chemical is calcium, especially in nerve cells which have developed sophisticated mechanisms for using calcium to control their function. Recently, new levels of complexity have been discovered, both in how cell calcium levels are modi ....The function of cells in the body is controlled by many hormones and neurotransmitters acting on the cell's surface. Hormones and transmitters mediate their effects by producing chemical signals within the cell that regulate its activities. One key cell signalling chemical is calcium, especially in nerve cells which have developed sophisticated mechanisms for using calcium to control their function. Recently, new levels of complexity have been discovered, both in how cell calcium levels are modified by hormones and transmitters and in how these complex calcium signals are used by cells to control their function. This project will investigate how hormones and transmitters can produce different types of calcium signals in nerve cells, and how these signals affect different aspects of the nerve cell's function. In particular, it will establish how two different types of specialised calcium stores within nerve cells are used by different classes of hormone and transmitter, and the distinct cellular functions these two calcium stores can regulate. The results will provide fundamental new information on how nerve cells control their activity and may help identify potential new targets for drugs.Read moreRead less
Cardiac-specific Therapy Targeting Hypertrophy And Apoptotis
Funder
National Health and Medical Research Council
Funding Amount
$542,683.00
Summary
We have discovered that certain pathological responses in the heart are mediated by an unusual type of signalling protein. The aim of the proposed studies is to determine whether this unusual signalling mechanism can provide a good target for development of new therapeutic approaches to prevent or treat heart failure.
The C-type Lectin, Mincle, Is A Macrophage Receptor For Candida Albicans.
Funder
National Health and Medical Research Council
Funding Amount
$465,210.00
Summary
The yeast Candida albicans is an important opportunistic infection that causes both mucosal and disseminated disease in patients whose innate or adaptive immune responses are impaired Infection and proliferation results in fungal colonisation of the tissues, and a variable degree of tissue damage. The latter is determined both by the virulence properties of the organism and by the genetic makeup of the host. This large, extracellular pathogen is eradicated from the body predominantly by acavenge ....The yeast Candida albicans is an important opportunistic infection that causes both mucosal and disseminated disease in patients whose innate or adaptive immune responses are impaired Infection and proliferation results in fungal colonisation of the tissues, and a variable degree of tissue damage. The latter is determined both by the virulence properties of the organism and by the genetic makeup of the host. This large, extracellular pathogen is eradicated from the body predominantly by acavenger (phagocytic) cells, which are also important in determining the severity of the associated tissue lesions. A phagocytic cell that is central to both innate and adaptive immune responses is the macrophage, which not only takes up and kills the yeast, but also is capable of of killing and digesting it, and presenting the components to cells of the adaptive immune system. This project is based on the postulate that the outcome and severity of infection is determined, at least in part, by the early functional response of the macrophage to the overall virulence properties of the yeast. The response is initiated by interactions with cell-surface receptors, and this study will show that a novel macrophage receptor, Mincle, is an important part of the innate immune response to fungal infections. We have shown that it is associated with differences in susceptibility to yeast infections in inbred mouse strains; it can discriminate between different isolates of the yeast; and it initiates the inflammatory signalling cascade. Our project will define the specific role of this receptor in fungal infection. The results will be important in understanding the basic biology of host resistance, and will offer new opportunities for therapeutic intervention by selectively blocking or modifying different activation pathways.Read moreRead less
Defining The Role Of GILZ In Inflammatory Arthritis
Funder
National Health and Medical Research Council
Funding Amount
$675,030.00
Summary
Corticosteroids are commonly used to treat inflammatory diseases such as arthritis. Their action is based on effects on natural inflammation control pathways. One such pathway is that mediated by the protein known as GILZ (glucocorticoid induced leucine zipper). The function of this protein in disease is not well understood, and the research proposed here will increase understanding of its role. This knowledge could yield new treatments for arthritis and other inflammatory diseases.