DNA-binding proteins regulate gene expression to co-ordinate our development and physiology. These proteins operate by recognizing specific control sequences in target genes and turning these genes on or off. It may be possible to artificially regulate specific genes to treat certain inherited disorders. One of the most common genetic diseases worldwide is inherited haemoglobinopathy. Mutations in the adult beta haemoglobin gene cause diseases such as sickle cell anaemia and beta thalassaemia. T ....DNA-binding proteins regulate gene expression to co-ordinate our development and physiology. These proteins operate by recognizing specific control sequences in target genes and turning these genes on or off. It may be possible to artificially regulate specific genes to treat certain inherited disorders. One of the most common genetic diseases worldwide is inherited haemoglobinopathy. Mutations in the adult beta haemoglobin gene cause diseases such as sickle cell anaemia and beta thalassaemia. These diseases can be seriously debilitating or lethal and often require lifelong treatment. Current treatments (such as repeated blood transfusion and subsequent iron chelation therapy) are demanding on the patient, expensive, and in the long run can be inneffective. Proposed future treatments involve reactivating normally silent haemoglobin genes (such as foetal haemoglobin) to compensate for the absence of adult beta haemoglobin. We have been studying a DNA-binding protein termed BKLF. We have shown that BKLF turns genes off and in particular we have shown using mammalian model systems that BKLF turns off the foetal haemoglobin gene. Inhibiting BKLF action therefore becomes an important goal, as this might lead to a reactivation of foetal haemoglobin to alleviate sickle cell anaemia and beta thalassaemia. We are seeking to understand the molecular mechanisms by which BKLF silences gene expression, to identify other proteins with which it operates, and to define their activities, in an effort to identify the best ways of inhibiting BKLF's action. Ultimately, studies on defined model genes such as the haemoglobin genes should elucidate general principles of gene regulation that may be useful in controlling gene expression in additional therapeutic or experimental contexts.Read moreRead less
Structural And Functional Studies On RNA Nuclear Retention Mediated By Paraspeckles: A Novel Gene Regulation
Funder
National Health and Medical Research Council
Funding Amount
$290,978.00
Summary
Dynamic interactions between proteins and nucleic acids are essential process in gene regulation, where aberrant regulation leads to various diseases including cancers. The project aims to examine the interactions between paraspeckle proteins and nucleic acid molecules via determination of the structures of protein-nucleic acid complexes at the atomic level. The results will provide a better understanding of a recently discovered gene regulation mechanism and a basis for new gene therapy.
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
Development Of An Immunotherapy Against Kgp Of Porphyromonas Gingivalis
Funder
National Health and Medical Research Council
Funding Amount
$495,710.00
Summary
Chronic periodontitis is an inflammatory disease of the supporting tissues of the teeth associated with specific bacteria, which results in the destruction of tooth support and ultimately leads to tooth loss. This project aims to develop an immunotherapy against the major virulence factor produced by bacteria associated with the disease. The immunotherapy will be evaluated in animal models of disease.
Great advances have been made in pharmaceutical design and discovery over the last 50 years. While drugs have traditionally been discovered using random screening of natural product libraries and chemical databases, new technologies in protein chemistry, structural and molecular biology have been adopted in efforts to speed the drug design process and increase its hit rate. In addition, our rapidly increasing knowledge of the molecular causes of many diseases provides us with many opportunities ....Great advances have been made in pharmaceutical design and discovery over the last 50 years. While drugs have traditionally been discovered using random screening of natural product libraries and chemical databases, new technologies in protein chemistry, structural and molecular biology have been adopted in efforts to speed the drug design process and increase its hit rate. In addition, our rapidly increasing knowledge of the molecular causes of many diseases provides us with many opportunities to develop therapeutics directed towards known molecular targets. Nevertheless, despite these advances, problems such as drug resistance and toxic side effects that compromise drug efficacy make it clear that there is a need for new classes of drugs with different modes of action. Because of their favourable properties, small-molecule drugs comprise by far the largest class of currently available therapeutics. However, in many cases, a drug derived from a protein may be preferable. The development of protein-based drugs is a youthful and rapidly expanding area of biotechnology, but to date, most studies have focused on targeting pathological events that occur on the outside of cells. We propose to use a combination of methods from molecular and structural biology, together with recently developed high-throughput screening techniques, to develop a generic protein drug scaffold that can be used as a template to develop therapeutics against a wide range of inappropriate interactions that may occur between molecules within cells.Read moreRead less
Design And Synthesis Of Peptide - Based Drugs For Multiple Sclerosis
Funder
National Health and Medical Research Council
Funding Amount
$351,000.00
Summary
Multiple sclerosis (MS) is an inflammatory disease of the central nervous system that affects ~1 million young adults worldwide. It is a debilitating disease for which there is currently no cure. The most effective treatment available, interferon-b (IFN-b) is useful for the treatment of some forms of the disease, reducing the relapse rate, that is the frequency of attacks or exacerbations of the disease, and delaying the time to onset of sustained progression of the disability. This treatment ma ....Multiple sclerosis (MS) is an inflammatory disease of the central nervous system that affects ~1 million young adults worldwide. It is a debilitating disease for which there is currently no cure. The most effective treatment available, interferon-b (IFN-b) is useful for the treatment of some forms of the disease, reducing the relapse rate, that is the frequency of attacks or exacerbations of the disease, and delaying the time to onset of sustained progression of the disability. This treatment may, however, cause adverse side effects, result in the development of antibodies that neutralise its function and is prohibitively expensive. In addition it does not slow the sustained progression of the disease in 20-40% of patients with the two most common types of MS and does not appear to directly affect deterioration of the protective layer around neurons, myelin. There is clearly a need for the development of therapeutics that address these issues and the drug leads to be developed in this project may help to overcome some of these shortfalls. While the immune system of a healthy individual is able to distinguish between foreign molecules and its own molecules, in MS the immune system fails to do this. An immune response against important proteins that form part of the protective myelin layer around neurons occurs. This means that the integrity of the protective layer is compromised. The peptide-based drugs that we plan to develop in this project are designed to interfere with the interaction between these important myelin proteins and their immune system targets. This will leave the myelin proteins to carry out their normal physiological roles and should therefore significantly slow, if not halt, progression of the disease. Given the prevalence of MS such a development could have a profound impact on the health and quality of life of many individuals and their families, and has the potential to substantially reduce the economic burden of this disease on the community.Read moreRead less
Affinity-based Profiling Of Bacterial Fe(III)-siderophore Receptors: Design Strategies For Antibiotics And Iron Overload
Funder
National Health and Medical Research Council
Funding Amount
$275,016.00
Summary
In order to establish an infection, bacteria compete with the host for iron, which is in scarce supply. To access iron, bacteria produce compounds called siderophores which bind iron strongly. The iron-siderophore complex, which is unique to each bacterium, is recognised by specific receptors at the bacterial cell-surface and imported for use. In this project, we are using modified siderophores as platforms for bacteria-specific drug design with the aim of producing new antibiotics.