A Bioinformatic Analysis And Structural Study On The Inositol Polyphosphate 5-phosphatases
Funder
National Health and Medical Research Council
Funding Amount
$421,320.00
Summary
Communication (or signaling) inside the cell enables the cell to respond to factors in its external environment, such as hormones or growth factors. The inositol phosphates and the phosphoinositides are signaling molecules that play an essential role in intracellular communication. The 5-phosphatases are able to modify these molecules and terminate, and in certain cases stimulate, signals. Failure to properly control intracellular signaling pathways may result in abnormal cell growth and cancer. ....Communication (or signaling) inside the cell enables the cell to respond to factors in its external environment, such as hormones or growth factors. The inositol phosphates and the phosphoinositides are signaling molecules that play an essential role in intracellular communication. The 5-phosphatases are able to modify these molecules and terminate, and in certain cases stimulate, signals. Failure to properly control intracellular signaling pathways may result in abnormal cell growth and cancer. Human 5-phosphatases are a complex family of enzymes: In addition to the region responsible for phosphatase activity (the catalytic domain) many members contain other protein modules . These associated domains may perform critical roles, such as regulating intracellular location and docking with other proteins. This project aims to perform a computational investigation of human 5-phosphatases and their associated domains. In particular we will search for novel phosphatases, investigate the evolutionary relationships between members of each domain family, and make testable predictions regarding the function of uncharacterized domains. This study will take advantage of data produced by the recently completed human genome project. The second aim of the project is to determine, using X-ray crystallography, the three-dimensional shape (or atomic structure) of a representative member of the 5-phosphatase family. Solving the structure of a 5-phosphatase at the atomic level is critical for understanding the nature of substrate specificity and for rational drug design.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
Regulation Of Dynamic Cell-cell Adhesions By Coordinated Action Of Lipid Kinases And Phosphatases
Funder
National Health and Medical Research Council
Funding Amount
$529,565.00
Summary
This research project studies the molecular mechanisms that allow cells to attach to, and recognize, one another. Such cell-to-cell adhesion is mediated by the cadherin family of molecules, which reside on the surfaces of cells. Cadherins allow cells to recognize one another and, upon recognition, to adhere to each other. By this means, populations of individual cells can be linked together into cohesive populations - i.e. the tissues and organs of the body. The importance of cadherin adhesion i ....This research project studies the molecular mechanisms that allow cells to attach to, and recognize, one another. Such cell-to-cell adhesion is mediated by the cadherin family of molecules, which reside on the surfaces of cells. Cadherins allow cells to recognize one another and, upon recognition, to adhere to each other. By this means, populations of individual cells can be linked together into cohesive populations - i.e. the tissues and organs of the body. The importance of cadherin adhesion is exemplified by the fact that disruption of cadherin adhesion contributes to many important diseases, especially inflammation and cancer. Thus understanding how cadherins hold cells together is necessary for us to understand the molecular basis of common diseases. In this project we study how cadherins signal to regulate cellular behaviour. We build on our recent discovery that E-cadherin can activate a lipid in the cell membrane, PIP3, that is known to be a key regulator of many cellular activities. We aim to understand how this signal is generated in response to E-cadherin adhesion and how it elicits normal cellular responses to cadherin adhesion.Read moreRead less
The Role Of Mal In Toll-like Receptor Signal Transduction Of The Pro-inflammatory Response.
Funder
National Health and Medical Research Council
Funding Amount
$472,500.00
Summary
Sepsis kills more people per year than the cancers of the breast, colon, prostate and pancreas combined. Sepsis occurs in 1 of 50 hospital admissions and is the leading cause of death n intensive care units. The instance of sepsis has doubled in the last decade and is expected to increase. One of the major causes of sepsis si lipopolysaccharide (LPS), the main constituent of gram-negative bacteria's cell wall, and the prototypic inducer of the pro-inflammatory response of the innate immune syste ....Sepsis kills more people per year than the cancers of the breast, colon, prostate and pancreas combined. Sepsis occurs in 1 of 50 hospital admissions and is the leading cause of death n intensive care units. The instance of sepsis has doubled in the last decade and is expected to increase. One of the major causes of sepsis si lipopolysaccharide (LPS), the main constituent of gram-negative bacteria's cell wall, and the prototypic inducer of the pro-inflammatory response of the innate immune system. Dysregulation of the pro-inflammatory response can lead to sepsis. Recently, the mammalian receptor for LPS was found to be Toll-like receptor (TLR)-4, the activation of which activates a signal transduction pathway that initiates the pro-inflammatory response. We have previously shown a key role for an adapter protein called Mal in mediating signal transduction pathways upon activation of TLR-4. Interaction of Mal with a key signal transduction mediator called TRAF6 has been shown to induce the activation of the pro-inflammatory response. Furthermore, Mal has been found to undergo degradation which may indicate a means of regulating the continued activation of the pro-inflammatory pathway. This research program will investigate the role of Mal in mediating signal transduction in TLR activated macrophages, key responsive cells of the innate immune system to microbial infection. A greater understanding of these processes will assist in the development of therapeutics to alleviate the consequences of microbial-induced inflammation, including chronic inflammatory diseases and sepsis.Read moreRead less
Molecular Investigations Of The Neuroprotective Activity Of Estrogen, Phytoestrogens, And Phytosterols
Funder
National Health and Medical Research Council
Funding Amount
$270,872.00
Summary
Estrogen protects women from heart and brain disease but more women will spend over a third of their lives in the postmenopausal state, which is characterized by reduced estrogen levels. Many studies suggest that estrogen-like compounds produced by plants may provide health benefits and alleviate the symptoms of menopause. We investigate the protective effects of such compounds in nerve cells, to address the unmet need for safe and effective prevention and treatment of neurological diseases.
Interactions Between IGFBP-3 And TGFbeta In The Inhibition Of Breast Cancer Cell Growth
Funder
National Health and Medical Research Council
Funding Amount
$662,970.00
Summary
A protein first identified by our research group, called insulin-like growth factor binding protein-3 or IGFBP-3, has been shown to be a potent inhibitor of the growth of cancer cells. High levels of IGFBP-3 in the bloodstream are associated with a decreased risk of several cancer types, including breast cancer. However, the way in which this protein prevents cancer cells from growing is poorly understood. This project will investigate an entirely novel idea, developed in our laboratory, that th ....A protein first identified by our research group, called insulin-like growth factor binding protein-3 or IGFBP-3, has been shown to be a potent inhibitor of the growth of cancer cells. High levels of IGFBP-3 in the bloodstream are associated with a decreased risk of several cancer types, including breast cancer. However, the way in which this protein prevents cancer cells from growing is poorly understood. This project will investigate an entirely novel idea, developed in our laboratory, that the actions of IGFBP-3 are intimately connected with the actions of another known cell growth inhibitor called transforming growth factor beta (TGFbeta). We have found that these two proteins initiate the same sequence of events leading to growth inhibition in breast cancer cells, and that a receptor protein required for TGFbeta activity is also needed for IGFBP-3 to be inhibitory. Our work has the potential to explain for the first time exactly how IGFBP-3 stops cancer cells from growing. This is important because it is an abundant protein in the body, and understanding how it acts may lead to the development of new approaches to cancer therapy that exploit our findings.Read moreRead less
Suppression Of Immune Toll-like Receptor (TLR) Signaling By Hepatitis B E Antigen (HBeAg)
Funder
National Health and Medical Research Council
Funding Amount
$542,320.00
Summary
Hepatitis B virus (HBV) infection is a major world-wide health problem, which the current treatment strategies are not ideal. Therefore understanding how HBV inteacts with the immune system is of critical importance to developing intervention strategies to promote better health outcomes. This grant will develop our novel findings that a protein produced by HBV 'blinds' the host immune system by producing a protein that blocks the innate immune response to allow HBV to replicate unchallenged.
Src Family Kinases: Regulation Of Phosphoinositol-3 Kinase Signaling And Autoimmune Disease Development.
Funder
National Health and Medical Research Council
Funding Amount
$526,683.00
Summary
The immune system has to be capable of responding to an unlimited array of pathogens, but at the same time remain unresponsive to, or tolerant of, self-antigens. A breakdown in the tolerance to self-antigens results in autoimmunity. Autoimmune disease includes more than 70 chronic disorders that affect about 1 in 20 people in the Western population. Improving our understanding of the mechanisms that underlie autoimmune disease is essential for the design of more successful treatments. The Lyn ty ....The immune system has to be capable of responding to an unlimited array of pathogens, but at the same time remain unresponsive to, or tolerant of, self-antigens. A breakdown in the tolerance to self-antigens results in autoimmunity. Autoimmune disease includes more than 70 chronic disorders that affect about 1 in 20 people in the Western population. Improving our understanding of the mechanisms that underlie autoimmune disease is essential for the design of more successful treatments. The Lyn tyrosine kinase is an enzyme that is found within blood cells. It participates in transmitting information across the cell membrane to turn off cellular responses. Studies in mutant mice have shown that Lyn is critically important for maintaining stability in the immune system. Mice that are unable to make Lyn protein (Lyn-deficient mice) as well as mice that express an activated form of the Lyn enzyme (Lyn-up mice) develop autoimmune disease with characteristics similar to the human autoimmune disease systemic erythematosus (SLE). These studies suggest that Lyn is an important severity gene in autoimmunity. The aim of this grant will be to identify Lyn-dependent signaling pathways that lead to autoimmune disease, with a major focus being on the lipid kinase pathway. We will use a combination of genetic and biochemical approaches to reveal critical genes and pathways. Cataloging the molecular changes related to alterations in Lyn activity will, we believe, provide insight into the genetic defects or signal perturbations underlying human autoimmune diseases. In this way, our study will aid in the diagnosis of human autoimmune diseases and uncover useful targets for more specific and effective treatments.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
Is Lyn Tyrosine Kinase A Predictor Of Severe, Persistent Multi-trait Asthma And Allergy?
Funder
National Health and Medical Research Council
Funding Amount
$250,250.00
Summary
Asthma is a major health problem in Australia affecting over 10% of the population at any time, and more than 25% of the population at one stage in their lives. Although the public perception is that asthma treatments have improved management of the disease, more than 700 people die from severe asthma each year and hospitalisation from exacerbation (sudden worsening) is one of the most costly components of the health care burden in Australia and most developed countries. Currently there are no m ....Asthma is a major health problem in Australia affecting over 10% of the population at any time, and more than 25% of the population at one stage in their lives. Although the public perception is that asthma treatments have improved management of the disease, more than 700 people die from severe asthma each year and hospitalisation from exacerbation (sudden worsening) is one of the most costly components of the health care burden in Australia and most developed countries. Currently there are no molecular markers that can predict who will get severe asthma and there are no specific treatments to reverse severe exacerbations. This project will use advanced molecular biology methods to examine whether a molecule called Lyn may be important. The Lyn tyrosine kinase is a member of a family of genes that participate in transmitting information across the cell membrane. This enzyme is expressed in blood cells, and is involved in mechanisms pertaining to infection, immunity and allergic responses. To further our understanding of the role of this enzyme in the context of the whole animal, we have generated mice that are unable to make Lyn protein (Lyn-deficient mice). In animal models of asthma we know that if Lyn is not functioning, severe and persistent asthma develops. We have also made preliminary studies that suggest that Lyn does not work properly in people who have been admitted to the emergency ward with life threatenting asthma. In this study we will examine in detail the role that Lyn plays in asthma and allergy, and we intend to identify the pathways that give rise to asthma in Lyn-deficient mice. We will also investigate our hypothesis that Lyn activity may be reduced or disregulated in patients with asthma and allergy. This research should lead to better predictive markers for severe asthma and also to improved and specific treatments.Read moreRead less