From Linkage To Genes Conferring Susceptibility To Schizophrenia: Investigation Of Candidate Genes On Chromosome 6p
Funder
National Health and Medical Research Council
Funding Amount
$462,250.00
Summary
Schizophrenia is a potentially disabling disorder with severe impact on the individual, the family and the community. The risk that a child born today will develop schizophrenia is about 1%. Genetic factors play a major predisposing role in schizophrenia, but environmental factors contribute as well. The molecular causes of schizophrenia are yet to be discovered, as knowledge about complex brain functions and their disorders is rapidly increasing. The identification and characterisation of genet ....Schizophrenia is a potentially disabling disorder with severe impact on the individual, the family and the community. The risk that a child born today will develop schizophrenia is about 1%. Genetic factors play a major predisposing role in schizophrenia, but environmental factors contribute as well. The molecular causes of schizophrenia are yet to be discovered, as knowledge about complex brain functions and their disorders is rapidly increasing. The identification and characterisation of genetic factors involved in brain function and dysfunction is likely to bring about novel insights into the neural and molecular mechanisms underlying schizophrenia. There is evidence, reported by several groups including our own, that genes, co-segregating with schizophrenia in families are located in a region on chromosome 6p. By fine-grain genetic dissection of this region, we and others have found that the gene coding for the protein dysbindin is associated with schizophrenia. Our aim is to identify the DNA variant(s) in the dysbindin gene, as well as variants in other candidate genes that may be located in chromosome 6p. We will use state-of-the art methods and information on genes and DNA variants, made available through the Human Genome Project. Once genetic variants are identified, we will analyse gene expression in post mortem brain tissue of persons with schizophrenia and study the distribution and function of the proteins coded by the identified genes. Our ultimate goal is to identify specific genetic factors involved in the brain dysfunction characterising schizophrenia. If successful, this should lead to clues about the causes of the disorder. In addition, the study will contribute to the development of methods for early diagnosis and prevention. Possibly, the most important outcome will be the identification of molecular targets for novel and more specific pharmacological treatments that may eventually replace current symptom-oriented antipsychotic medications.Read moreRead less
The Putative Drug Metabolising Enzyme SULT4A1 Is A Sulfotransferase Inhibitor
Funder
National Health and Medical Research Council
Funding Amount
$467,851.00
Summary
The sulfotransferase SULT4A1 is a novel protein found predominantly in neurons but its function is unknown. This project will investigate the mechanisms that the body uses to regulate the levels of this protein and how it may interfere with other enzymes essential for metabolising hormones and neurotransmitters.
Developing Novel Molecules That Target Hormone Receptors As An Alternative Cancer Therapy
Funder
National Health and Medical Research Council
Funding Amount
$459,867.00
Summary
A promising class of cancer drugs target heat shock protein 90 (Hsp90) and prevent Hsp90 from maintaining its ~100 proteins involved in cell growth. However, all current Hsp90 chemotherapeutics non-selectively target proteins maintained by Hsp90, and induce a cell rescue mechanism involving Hsp70. We describe the development of a novel molecule that will selectively control cell growth and prevent cell rescue via a unique Hsp90 regulated mechanism.
Peptide Toxins From Animal Venoms Specifically Targeting Voltage-gated Sodium Channels As Novel Analgesics And Pesticides
Funder
National Health and Medical Research Council
Funding Amount
$316,449.00
Summary
This project aims to understand how certain animal toxins that cause analgesic and pesticidal effects in model animals interact with biological ion channels in atomistic detail using computational techniques. By understanding the detailed molecular interactions involved in the binding of the toxins to channels, toxin variants with improved potency and specificity may be designed as promising templates for novel analgesics and pesticides.
Alzheimer's, Huntington's and Parkinson's diseases involve the formation of protein aggregates, termed amyloid. The formation of amyloid leads to cell death and neurodegeneration. The most important cellular events perturbed by the formation of amyloid aggregates are unclear. Recent evidence suggests that sterols (including cholesterol) have an important role in cellular toxicity. This study will examine the molecular basis for this, enhancing our understanding of the amyloid diseases and could ....Alzheimer's, Huntington's and Parkinson's diseases involve the formation of protein aggregates, termed amyloid. The formation of amyloid leads to cell death and neurodegeneration. The most important cellular events perturbed by the formation of amyloid aggregates are unclear. Recent evidence suggests that sterols (including cholesterol) have an important role in cellular toxicity. This study will examine the molecular basis for this, enhancing our understanding of the amyloid diseases and could suggest novel therapeutic avenues.Read moreRead less
Discovery And Mechanisms Of Host Cell Factors In HIV Uncoating
Funder
National Health and Medical Research Council
Funding Amount
$635,098.00
Summary
HIV entry into the host cell involves release of its capsid, a protein shell protecting the viral genome. The capsid hijacks host proteins to cloak itself from cellular defenses while the cell has evolved sensors that can block viral infection. This proposal aims to discover proteins involved in this arms race between host and virus and decipher how they control capsid disassembly. This insight will help design new drugs against HIV infection and new ways to deliver genes for gene therapies.
Pathogenic And Adaptive Molecular Interactions With Mutant Huntingtin Exon 1
Funder
National Health and Medical Research Council
Funding Amount
$727,117.00
Summary
This project aims to determine how the gene mutation that causes Huntington’s disease (HD) damages cells in the brain. The diseased gene creates a protein that is abnormally sticky, which causes it to form clumps. Our goal is to determine the components of the cell that are disrupted and damaged as clumping happens. Understanding this link will enable therapeutics to be logically designed in efforts to prevent harm to the brain, potentially before symptoms are evident.
Characterisation Of A Novel Human Neuromuscular Disease Associated With Deficiency Of The Syntrophins And Dystrobrevin.
Funder
National Health and Medical Research Council
Funding Amount
$284,069.00
Summary
The muscular dystrophies are a group of hereditary muscle diseases which can result in severe and progressive muscle weakness. Children with muscular dystrophy have significant and worsening disabilities; many are unable to walk and, in severe cases, the weakness impairs the muscles of breathing resulting in death at an early age. The more common muscular dystrophies present in early childhood; however some forms of muscular dystrophy are so severe that muscle weakness is obvious at birth, affec ....The muscular dystrophies are a group of hereditary muscle diseases which can result in severe and progressive muscle weakness. Children with muscular dystrophy have significant and worsening disabilities; many are unable to walk and, in severe cases, the weakness impairs the muscles of breathing resulting in death at an early age. The more common muscular dystrophies present in early childhood; however some forms of muscular dystrophy are so severe that muscle weakness is obvious at birth, affected babies are never able to breathe adequately, and die during the first weeks of life. No specific treatment is currently available. Until recently the underlying gene and protein abnormalities resulting in the majority of cases of muscular dystrophy were unknown and hence definitive diagnosis and prenatal diagnosis was not possible. We have recently identified deficiency of a group of muscle proteins, the syntrophins and dystrobrevin, in 15 children with severe weakness, in whom the cause was previously unknown. This group of patients represent the first examples of a novel neuromuscular disorder. We will now identify the disease-causing genetic mutations in these patients and determine how abnormalities in these muscle proteins lead to muscle weakness and degeneration. This research will have immediate application to clinical practice as we will be able to give the childrens' families accurate information about the risk to future offspring and offer prenatal diagnosis. In addition, it will provide new and important information concerning the normal function of human skeletal muscle, which can be used to develop therapies for affected patients.Read moreRead less
Developing Drugs To Prevent Prostate Cancer Spread.
Funder
National Health and Medical Research Council
Funding Amount
$99,248.00
Summary
Current therapies for prostate cancer lose their efficacy as the cancer advances. Moreover, despite the spread of cancer being the major cause of prostate cancer mortality, there is no therapy available which selectively targets this process, thus new agents are needed. By using computer modelling to predict molecules that bind to the cell surface protein CD151 and testing these in biological assays, we aim to discover molecules that reduce cell migration of prostate cancer and that can be devel ....Current therapies for prostate cancer lose their efficacy as the cancer advances. Moreover, despite the spread of cancer being the major cause of prostate cancer mortality, there is no therapy available which selectively targets this process, thus new agents are needed. By using computer modelling to predict molecules that bind to the cell surface protein CD151 and testing these in biological assays, we aim to discover molecules that reduce cell migration of prostate cancer and that can be developed into anti-migration drugs.Read moreRead less
Insulin-like Growth Factor (IGF)-II Binding Specificity Of IGF Binding Protein-6: Structural And Functional Studies.
Funder
National Health and Medical Research Council
Funding Amount
$265,630.00
Summary
Insulin-like growth factor II (IGF-II) is a protein which is involved in normal growth. However, in some circumstances it may also stimulate cancer growth. IGF binding protein-6 (IGFBP-6) binds to IGF-II and stops its activity. One of the major challenges of modern biology is understanding why some proteins bind to other proteins. Proteins fold in various ways and have specific three-dimensional structures. Two proteins which bind strongly to each other have structures which fit each other like ....Insulin-like growth factor II (IGF-II) is a protein which is involved in normal growth. However, in some circumstances it may also stimulate cancer growth. IGF binding protein-6 (IGFBP-6) binds to IGF-II and stops its activity. One of the major challenges of modern biology is understanding why some proteins bind to other proteins. Proteins fold in various ways and have specific three-dimensional structures. Two proteins which bind strongly to each other have structures which fit each other like a 'lock and key'. The aim of this project is to understand how IGFBP-6 binds to IGF-II by looking at its three-dimensional structure. Using this information, it may be possible to develop new treatments which can inhibit IGF-II activity and therefore may be useful in the treatment of some cancers.Read moreRead less