Schizophrenia affects, on average, 1% of the population over a lifetime and accounts for 2.6% of the global burden of disease and disability, according to a joint study by the World Health Organization and the World Bank. It is a complex disorder involving both genetic and environmental risk factors, but the specific causation remains poorly understood. People with schizophrenia experience symptoms such as delusions and hallucinations, distorted perception of reality, and progressive loss of mot ....Schizophrenia affects, on average, 1% of the population over a lifetime and accounts for 2.6% of the global burden of disease and disability, according to a joint study by the World Health Organization and the World Bank. It is a complex disorder involving both genetic and environmental risk factors, but the specific causation remains poorly understood. People with schizophrenia experience symptoms such as delusions and hallucinations, distorted perception of reality, and progressive loss of motivation, which disrupt personal development. Recent research demonstrates that underlying cognitive impairments, affecting reasoning, memory, planning ability and information processing, are at the core of the disorder and account for a high proportion of these handicaps. In a study involving 112 families with members suffering from schizophrenia, Western Australian researchers carried out detailed investigations of brain cognitive functioning, coupled with a complete genome scan. They identified, in about 50% of these families, a variety of schizophrenia characterized by multiple cognitive deficits, which turned out to be linked to a particular segment of chromosome 6. It was exactly in the chromosomal region where US investigators had previously found genetic linkage with the symptoms of schizophrenia in a large series of Irish families. In this project, the Western Australian and US teams, together with a group of Dutch researchers, will embark on a joint search for the gene (or genes) on chromosome 6, contributing to cognitive deficits in schizophrenia. They will assess a further large series of patients and controls, and conduct molecular genetic studies aiming to pinpoint the specific gene defect or variant. If successful, the project will have far-reaching implications for defining novel drug targets and treatment strategies for this disabling disorder.Read moreRead less
Discovery And Analysis Of Vertebrate Intestinal Development Genes That May Play A Role In Colon Cancer
Funder
National Health and Medical Research Council
Funding Amount
$376,613.00
Summary
Colorectal cancer (CRC) causes more cancer deaths in Australia than any other cancer. While early detection improves survival rate, nearly half of all CRC patients succumb to the disease within five years. In general, metastatic CRC is resistant to chemotherapy and radiotherapy and new therapies are required. An increased knowledge of the processes that contribute to the malignant state is likely to suggest new targets for treatment. CRC, like all cancer, is the result of genetic abnormalities ( ....Colorectal cancer (CRC) causes more cancer deaths in Australia than any other cancer. While early detection improves survival rate, nearly half of all CRC patients succumb to the disease within five years. In general, metastatic CRC is resistant to chemotherapy and radiotherapy and new therapies are required. An increased knowledge of the processes that contribute to the malignant state is likely to suggest new targets for treatment. CRC, like all cancer, is the result of genetic abnormalities (mutations) that are acquired over the course of a lifetime. Together the mutated genes produce changes in cell behaviour in processes such as growth, migration, angiogenesis (the ability to attract a blood supply) and cell death. All of these processes are active during normal development of a vertebrate organism, but are generally shutdown in the adult state, except in cancer. In this study we will analyse a group of genes that we have recently shown to be indispensable for normal intestinal development in zebrafish. Zebrafish are small tropical fish that are used frequently for genetic studies. They are very closely related to mammals and it has been shown that the genetic pathways that control the development of this animal are highly conserved in fish and mammals. Importantly, the genetic pathways that lead to cancer in humans are also strikingly similar in zebrafish. Our experiments will use mouse models to discover whether the zebrafish genes we have identified can lead to cancer when they are aberrantly expressed in the intestines of mice. Any genes that are found to contribute to the development of cancer in these models could become potential new targets for cancer therapy.Read moreRead less
The Cellular And Molecular Basis To The Paradox Of Positive Versus Negative T Cell Selection
Funder
National Health and Medical Research Council
Funding Amount
$278,090.00
Summary
The protection against disease requires the generation of white blood cells called T lymphocytes that are produced in the thymus. Each T cell has a specific surface receptor, generated by random gene switching, that can react against foreign pathogens. Since there is a very high conservation of molecules used in all organisms, some of these receptors could by chance also react against normal cells in the host. Eliminating all such self-reactive cells would mean, however, the repertoire remaining ....The protection against disease requires the generation of white blood cells called T lymphocytes that are produced in the thymus. Each T cell has a specific surface receptor, generated by random gene switching, that can react against foreign pathogens. Since there is a very high conservation of molecules used in all organisms, some of these receptors could by chance also react against normal cells in the host. Eliminating all such self-reactive cells would mean, however, the repertoire remaining for eliminating infection would be too low and immunodeficiency develops. This project investigates the mechanisms controlling the balance between defence infection and the need to prevent immune-based self destruction termed autoimmunity.Read moreRead less
What Triggers Complex Regional Pain Syndrome After Minor Injury?
Funder
National Health and Medical Research Council
Funding Amount
$958,898.00
Summary
Most people recover from minor trauma but some develop very disabling, difficult to treat, costly pain syndromes. We can identify those at high risk of developing such a syndrome after wrist fracture. By comparing inflammation, immune system function, stress, brain function and behaviour between high and low risk patients, we will take a major step towards understanding, preventing and treating these syndromes.
In Parkinson's disease only specific brain cells die, these cells are unusual in that they contain a dark coloured pigment called neuromelanin. The presence of this pigment is thought to play a role in the death of these cells. Evidence from many different diseases has demonstrated that a type of cell damage called oxidative damage is caused by an increase in tissue iron levels. Iron levels are increased in the brains of persons who have died with Parkinson's disease but only in the part of the ....In Parkinson's disease only specific brain cells die, these cells are unusual in that they contain a dark coloured pigment called neuromelanin. The presence of this pigment is thought to play a role in the death of these cells. Evidence from many different diseases has demonstrated that a type of cell damage called oxidative damage is caused by an increase in tissue iron levels. Iron levels are increased in the brains of persons who have died with Parkinson's disease but only in the part of the brain which contains neuromelanin. This increase in iron is thought to lead to oxidative damage and thus cell death in Parkinson's disease. Why iron should be increased specifically in this part of the brain is unknown but it has been shown that neuromelanin binds tissue iron and that the interaction between iron and neuromelanin can result in tissue damage. These events are suggested to underlie the specific vulnerability of the neuromelanin-containing cells in Parkinson's disease. However as yet very little is known about this pigment or how it interacts with iron. This research investigates neuromelanin in the normal brain and in the brain of persons who have died with Parkinson's disease. The project aims to demonstrate how neuromelanin interacts with iron and how neuromelanin, both in the presence and absence of iron, can influence oxidative cell damage. The use of human neuromelanin makes this research unique and it will provide important and novel information regarding the role of this pigment in the aetiology of this devastating disease.Read moreRead less
Ghrelins Novel Neuroprotective Effects In Parkinsons Disease Are Mediated By AMP-activated Protein Kinase (AMPK).
Funder
National Health and Medical Research Council
Funding Amount
$400,885.00
Summary
Studies show that body mass index, midlife adiposity and diabetes are associated with Parkinson's disease (PD). During obesity there is a dramatic change in nutritional information, such as hormones, sugars and fats, carried in the blood. This proposal explores how this altered nutritional information in obesity kills the brain cells associated with PD. It will examine how ghrelin, a metabolic hormone inversely related to obesity, influences and protects brain cell activity in models of PD.
Antibiotic Resistance And Multiple Antibiotic Resistance In Human Commensal Escherichia Coli In Australia
Funder
National Health and Medical Research Council
Funding Amount
$509,202.00
Summary
Antibiotic resistance, particularly resistance to all or nearly all of the antibiotics available for treatment is now very common and impacts heavily on the treatment of bacterial infections. This project will track resistance genes in reservoirs where antibiotic resistance genes may be present in high concentrations as these are a likely source of the resistance genes in disease-causing bacteria. One such reservoir, the bacteria in the intestines of healthy humans will be examined.
Cysteine Rich Secretory Proteins (Crisp) Are Ion Channel Regulators With Essential Roles In Male Fertility
Funder
National Health and Medical Research Council
Funding Amount
$531,696.00
Summary
Male infertility affects 1 in 20 Australian men and for the majority of other men, contraception is an issue at some point in their lives. Despite this, relatively little is known about the processes of sperm production and fertilization. As such, there is an urgent need for futher research if we are to hope to develop diagnostics, targeted therapeutics and to take advantage of the growing awareness by pharmaceutical companies of the market for male gamete based contraceptives. The cysteine rich ....Male infertility affects 1 in 20 Australian men and for the majority of other men, contraception is an issue at some point in their lives. Despite this, relatively little is known about the processes of sperm production and fertilization. As such, there is an urgent need for futher research if we are to hope to develop diagnostics, targeted therapeutics and to take advantage of the growing awareness by pharmaceutical companies of the market for male gamete based contraceptives. The cysteine rich secretory proteins (Crisps) are a group of proteins which show a remarkable bias to the male reproductive tract. All four are incorporated into sperm. Recently published data from us indicates that they have the ability to regulated calcium flow in sperm and as such sperm activity. The aim of the current proposal is to explore the biological relevance of one domain of Crisp proteins using animal models, in vitro sperm tests and through an analysis of ion flux and phosphorylation status under conditions of altered Crisp-1 and -2 content. The data generated from this project will make a significant contribution to the development of novel male gamete based contraceptives for use by either men or women. In addition, through the attainment of a greater understanding of sperm development and function, we will be able to more precisely define types of infertility, thus allowing for the development of more targeted therapies. The development of Crisp agonists or antagonists may also be of value in the treatment of other cilia disorders including primary cilia dykinesia and cystic fibrosis.Read moreRead less