Novel Mechanisms In Regulating Cytokine Secretion In The Inflammatory Response
Funder
National Health and Medical Research Council
Funding Amount
$323,160.00
Summary
Macrophages are key cells in the immune and inflammatory response. They play a role in many biological processes including wound healing and resistance to tumours and infections. It is also a major cell involved in mediating inflammation and tissue damage in chronic inflammatory diseases such as atherosclerosis and rheumatoid arthritis. The macrophage's role in these processes is achieved in large part by secreting enzymes and other proteins called cytokines to the outside of the cell. These cyt ....Macrophages are key cells in the immune and inflammatory response. They play a role in many biological processes including wound healing and resistance to tumours and infections. It is also a major cell involved in mediating inflammation and tissue damage in chronic inflammatory diseases such as atherosclerosis and rheumatoid arthritis. The macrophage's role in these processes is achieved in large part by secreting enzymes and other proteins called cytokines to the outside of the cell. These cytokines are synthesized by the macrophage and travel through a secretory pathway in the cell, in order to be released to the outside of the cell. There are various quality control mechanisms along the pathway which ensure only correctly made functional protein is secreted out of the cell. One cytokine, called macrophage inhibitory cytokine is produced by the immune cells called macrophages only when they become activated to mount an immune response against invading pathogens. The cell uses a novel mechanism to ensure the quality control of this cytokine. The propeptide of this cytokine targets incorrectly folded cytokine to a protein complex called the proteasome for degradation. This prevents secretion of inactive cytokine. Additionally, the propeptide of the cytokine helps secretion from macrophages by a novel mechanism. Because of these characteristics the cytokine provides a good model to study secretion from macrophages under pro- and anti-inflammatory conditions. In addition, demonstrating that activation of the macrophages causes a major upregulation in the synthesis and secretion of cytokines by novel mechanisms, will further our understanding of how the macrophage operates in fulfilling its role in the immune response.Read moreRead less
Molecular Analysis Of Alpha-1-Antitrypsin Misfolding: A Cause Of Alpha-1-antitrypsin Deficiency
Funder
National Health and Medical Research Council
Funding Amount
$255,837.00
Summary
Antitrypsin deficiency occurs in approximately 1 in 1800 live births. It is the most common genetic cause of liver disease in children and the debilitating lung disease emphysema in adults. Antitrypsin is produced in the liver and secreted into the circulation. Its primary role is to inhibit the degradative enzyme elastase which attacks the tissues of the lung. A deficiency in Antitrypsin leads to uncontrolled elastase activity which destroys the lung tissue so causing emphysema. The deficiency ....Antitrypsin deficiency occurs in approximately 1 in 1800 live births. It is the most common genetic cause of liver disease in children and the debilitating lung disease emphysema in adults. Antitrypsin is produced in the liver and secreted into the circulation. Its primary role is to inhibit the degradative enzyme elastase which attacks the tissues of the lung. A deficiency in Antitrypsin leads to uncontrolled elastase activity which destroys the lung tissue so causing emphysema. The deficiency is commonly caused by Antitrypsin being unable to enter the circulation. This is due to mutations within the Antitrypsin molecule which cause the protein to adopt an incorrect three-dimensional structure. This causes the protein to form long chains within the liver, which in turn damage the liver cell. There are no specific treatments for Antitrypsin deficiency, this partly reflects our lack of understanding of the molecular basis of the disease. This project examines the effects of the mutations upon the folding of Antitrypsin so that we can understand how these long protein chains form. Using a range of biochemical techniques we will monitor structural changes within the normal and abnormal proteins as they fold to determine how the mutations disrupt the process. These data will allow us to begin to rationally design inhibitors which will prevent the formation of the long chains, which we hope will aid in the treatment of patients with Antitrypsin deficiency. This increased understanding of Antitrypsin deficiency may also benefit other disease processes where similar protein misfolding occurs such as amyloid and prion diseases.Read moreRead less
Both human and viral genetic materials (ribonucleic acids, RNA) are made up of 4 different basic residues, namely A, U, G and C. Combination of any three of these ribonucleic acids residues is known as codon , which is essential to target one of the twenty amino acids to the host cell machinery for the making of proteins. Eighteen out of these twenty amino acids can be represented by more than one codon during the making of proteins. Interestingly, human and viral proteins, such as HIV-1, utilis ....Both human and viral genetic materials (ribonucleic acids, RNA) are made up of 4 different basic residues, namely A, U, G and C. Combination of any three of these ribonucleic acids residues is known as codon , which is essential to target one of the twenty amino acids to the host cell machinery for the making of proteins. Eighteen out of these twenty amino acids can be represented by more than one codon during the making of proteins. Interestingly, human and viral proteins, such as HIV-1, utilise two completely different subsets of codons (codon bias) for the synthesis of their respective proteins. The objective of this proposal is to delineate the functional requirement of this codon bias in HIV-1 replication cycle. Results from this work will identify novel elements that may be used for the design of novel antiretroviral strategy. Furthermore, lesson learned from this project will also provide important clues to improve the efficacy and safety of the design of current retroviral gene delivery vector.Read moreRead less
Mechanism Of Interaction Of VWC Domains And Consequence For Protein Function
Funder
National Health and Medical Research Council
Funding Amount
$516,803.00
Summary
More than 1000 proteins contain a type of module known as the VWC domain. These domains are discreet sections of the protein that are very important for how the protein works. Proteins containing this domain are involved in normal functioning of the human body and in diseases of the nervous system and blood, among others. The main function of the VWC domain is to link proteins together in complexes. How this is achieved is not known and is what we aim to discover.