Members Of The CMRF-35 Leukocyte Receptor Complex On Human Chromosome 17q22-24 Modulate Immune Function
Funder
National Health and Medical Research Council
Funding Amount
$489,750.00
Summary
We have identified and characterized a group of proteins on the surface of different white blood cells called the CMRF-35 molecules. We hypothesize that these molecules play a role in regulating an immune response by acting as thermostat molecules i.e. molecules able to trigger or inhibit the immune response. This project aims to define the role of two of these molecules in regulating white blood cells in their response to foreign molecules or antigens. This project will have significant impact ....We have identified and characterized a group of proteins on the surface of different white blood cells called the CMRF-35 molecules. We hypothesize that these molecules play a role in regulating an immune response by acting as thermostat molecules i.e. molecules able to trigger or inhibit the immune response. This project aims to define the role of two of these molecules in regulating white blood cells in their response to foreign molecules or antigens. This project will have significant impact on understanding whether these triggering and inhibitory signals initiated from the CMRF-35 molecules effects i) how the cells divide, ii) what molecules are secreted by the cells, iii) whether the cells can mature or iv) whether a cell survives or dies. Some of the molecules involved in sending these signals will be identified. The ability to trigger or inhibit cellular effects through these molecules may be important in some forms of myeloid leukemia and in the ability to help manipulate the immune response to fight tumors.Read moreRead less
Characterisation Of A Signal Transduction Pathway In The Early Embryo
Funder
National Health and Medical Research Council
Funding Amount
$208,500.00
Summary
The creation of embryos in the lab is important in assisted reproductive technology (ART) and potentially in cell therapies using embryonic stem cells. Yet, the development of the early embryo is not well understood. Creation of embryos in the lab is expensive and much of this cost is related to the relative inefficiency of the technology due to the high mortality of the resulting embryos. Typically, 45 - 80% of embryos produced by ART do not survive the first week. Hormones are essential chemic ....The creation of embryos in the lab is important in assisted reproductive technology (ART) and potentially in cell therapies using embryonic stem cells. Yet, the development of the early embryo is not well understood. Creation of embryos in the lab is expensive and much of this cost is related to the relative inefficiency of the technology due to the high mortality of the resulting embryos. Typically, 45 - 80% of embryos produced by ART do not survive the first week. Hormones are essential chemical messengers that regulate the normal functions of the body. Early embryo development is dependent on the action of special hormones that are produced by the embryonic cells themselves. The actions of these hormones are necessary for their normal survival. ART compromises the production and action of several of these hormones. Currently, there is not a detailed picture of how these embryonic hormones act on the embryo to promote their survival. Cells respond to outside hormones by changing the activity of a number intracellular proteins that act as on-off switches. The combinatorial pattern of 'switch' settings is modified by hormones, which in turn can act to change the pattern of gene expression. This project will extend our extensive studies on the nature of action of the well-described embryonic hormone known as PAF. The mechanism by which this hormone acts to signal changes in the pattern of the embryo's gene expression will be investigated. An understanding of how these embryonic hormones work will in the future allow for significant improvements in embryo viability.Read moreRead less
Defining The Genetic And Environmental Factors That Cause Abnormal Vertebral Segmentation During Embryogenesis
Funder
National Health and Medical Research Council
Funding Amount
$724,147.00
Summary
Many birth defects cause vertebral malformations along the spinal column. They originate as the fetus forms, and may be caused by gene mutation or environmental factors. Whilst studying one type of vertebral malformation we have found a genetic cause for 30% of cases. We will investigate the genetic and environmental cause of the remainder. We will look for new genes causing this disease, and use a mouse model to learn how low oxygen levels during pregnancy causes such malformations
Loss Of Cytostatic Regulation By TGF-beta During EGFR-driven Tumor Development
Funder
National Health and Medical Research Council
Funding Amount
$605,031.00
Summary
Growth factor and cytokine signalling networks control many aspects of cell behaviour such as proliferation, survival, migration, invasive capabilities, transformation and differentiation. In normal cells, these complex signalling pathways are tightly regulated. Alterations of these signals are often found to cause, directly or indirectly, tumour formation. Transforming Growth Factor-b (TGF-b) and Epidermal Growth Factor (EGF) signalling pathways are both independently implicated as key regulato ....Growth factor and cytokine signalling networks control many aspects of cell behaviour such as proliferation, survival, migration, invasive capabilities, transformation and differentiation. In normal cells, these complex signalling pathways are tightly regulated. Alterations of these signals are often found to cause, directly or indirectly, tumour formation. Transforming Growth Factor-b (TGF-b) and Epidermal Growth Factor (EGF) signalling pathways are both independently implicated as key regulators in tumour formation and as such they are potential therapeutic targets. However, while both pathways have been studied extensively, little is known about the cross-talk between the TGF-b and EGF pathways. This project will establish the generality of a new tumor signaling axis, namely EGFR-Stat3-Smad7-TGF-b in EGFR-overexpressing tumors. Practically, it will provide guidelines for the development of new approaches for treating effectively the EGFR-driven tumors.Read moreRead less
Validation Of Stat3 As A Therapeutic Target In Diseases Arising From Its Inappropriate Activation By Gp130 Cytokines
Funder
National Health and Medical Research Council
Funding Amount
$674,142.00
Summary
Stomach cancer is the third most prevalent cancer in the Western World and result in the yearly death of several thousand people in Australia alone. We have discovered a specifice gene mutation of a receptor molecule called gp130 that results in the formation of stomach cancer in mice. We are now aiming to understand the exact molecular events by which this mutation results in the uncontrolled growth of stomach lining cells. We will employ a number of strategies to establish molecularly the exte ....Stomach cancer is the third most prevalent cancer in the Western World and result in the yearly death of several thousand people in Australia alone. We have discovered a specifice gene mutation of a receptor molecule called gp130 that results in the formation of stomach cancer in mice. We are now aiming to understand the exact molecular events by which this mutation results in the uncontrolled growth of stomach lining cells. We will employ a number of strategies to establish molecularly the extent to which this mouse model is informative for gastric cancer inhuman. In aprticular we will identify the genes that are involved in the progression of the disease. One important focus of the project is to see whether or not the moelcule (called Stat3) whose aberrant activation triggers the disease in the mouse could provide a future pharmacological target for intervention with the disease. Similarly with expertise of CIB, we will investigate with novel proteomics techniques whther we can identify a protein in the serum of these mice, which could give us aclue of whether or not the mouse ahs already developed disease. Such a protein could be of potentail diagnostic importance in the future to screen human for gastric cancer which in its eraly stages is usually without any clinical symptoms. In a related Aim we will find out the gene that can genetically cooperate with Stat3 and that is required to enable survival of newborn mice. It may well turn out mOur proposal combines the expertise of the two investigators in signal transduction and that this gene may be an important determinant to ensure that Stat3 triggers physiological rather than pathological responses in many differnet organs.Read moreRead less
Characterization Of HLS5, A Novel Tumor Suppressor Gene
Funder
National Health and Medical Research Council
Funding Amount
$406,980.00
Summary
HLS5 is a novel gene that we recently discovered in our laboratory. Preliminary investigations suggest that HLS5 is similar to a family of genes which act as DNA regulators. We have shown that HLS5 is found on a region of chromosome 8 which is often deleted in human cancers, suggesting that HLS5 is a new tumour suppressor gene i.e.. damage to this gene may be responsible for the formation of certain types of cancer (specifically breast and prostate). Other evidence to support the claim that HLS5 ....HLS5 is a novel gene that we recently discovered in our laboratory. Preliminary investigations suggest that HLS5 is similar to a family of genes which act as DNA regulators. We have shown that HLS5 is found on a region of chromosome 8 which is often deleted in human cancers, suggesting that HLS5 is a new tumour suppressor gene i.e.. damage to this gene may be responsible for the formation of certain types of cancer (specifically breast and prostate). Other evidence to support the claim that HLS5 is a tumour suppressor gene comes from the proteins it associates with these partner molecules are involved in DNA repair or DNA regulation. When we introduced HLS5 into cancer cells, it slowed their growth and reduced their ability to form tumours. The aim of this project therefore, is to undertake a detailed analyses of the HLS5 gene and to determine the function of its protein product. A combination of approaches will be used in this study. We will: (i) alter the amount of HLS5 expression in cancer cells, (ii) characterize the proteins which bind to HLS5, (iii) determining where HLS5 localizes in the cell, (iv) analyze mice with lack the gene for HLS5, (v) assess the involvement of HLS5 in a human leukemia (vi) analyze HLS5 messenger RNA which produces the protein, and (vii) determining the structure of HLS5 protein. These studies should provide valuable information on how HLS5 functions, as well as its role in cancer formation.Read moreRead less
Apoptosis is a fundamental mechanism in regulating normal development and preventing cancer. Cancer cells must avoid apoptosis and also adapt to harsh metabolic environments in order to survive in the absence of effective nutrient supply and to resist the action of certain drugs. This project will provide a detailed analysis of metabolic changes allowing cells to survive long periods when the apoptotic process is absent and nutrients are limiting.
Specificity Of Smad Proteins In Transforming Growth Factor-beta Signaling
Funder
National Health and Medical Research Council
Funding Amount
$212,036.00
Summary
Transforming growth factor-betas (TGF-beta) regulate a fascinating array of cellular processes including cell proliferation, differentiation, migration, organization and death, as well as affect a wide range of biological functions, such as embryonic development, hematopoiesis and immune and inflammatory responses. Given the multifunctional nature of TGF-beta action, it is not surprising that the disruptions of TGF-beta functions have been implicated in many human disorders, particularly in colo ....Transforming growth factor-betas (TGF-beta) regulate a fascinating array of cellular processes including cell proliferation, differentiation, migration, organization and death, as well as affect a wide range of biological functions, such as embryonic development, hematopoiesis and immune and inflammatory responses. Given the multifunctional nature of TGF-beta action, it is not surprising that the disruptions of TGF-beta functions have been implicated in many human disorders, particularly in colorectal and pancreatic cancers. The Smad proteins (there are ten of them) are critical components of TGF-beta cellular actions. In fact, Smad4 also called DPC4 for deleted in pancreatic carcinoma locus 4. This project addresses how each Smad protein works at molecular level in the cell, and which part of biological functions it regulates. Collectively, the outcomes of the project may provide clear and specific molecular targets to treat TGF-beta related diseases such as colorectal and pancreatic cancers.Read moreRead less