The Developmental Vitamin D Model (DVD) As An Animal Model For Schizophrenia
Funder
National Health and Medical Research Council
Funding Amount
$258,075.00
Summary
Most Australians have the opportunity to enjoy the natural benefits of sunlight, however many Australians lack vitamin D. We have shown that even in Queensland, the so-called Sunshine State, vitamin D levels in the middle of winter are below World Health Organisation recommended levels. We are exploring low maternal vitamin D as a biological explanation for the universal phenomena worldwide of a 7-10% increase in the incidence of patients born with schizophrenia in the colder months of the year. ....Most Australians have the opportunity to enjoy the natural benefits of sunlight, however many Australians lack vitamin D. We have shown that even in Queensland, the so-called Sunshine State, vitamin D levels in the middle of winter are below World Health Organisation recommended levels. We are exploring low maternal vitamin D as a biological explanation for the universal phenomena worldwide of a 7-10% increase in the incidence of patients born with schizophrenia in the colder months of the year. Schizophrenia is a developmental disease that presents in adolescence and affects about 1% of the world's population. To date we have shown increased amounts of schizophrenia in offspring from mothers that had low blood vitamin D levels during pregnancy or who had inadequate vitamin D intake. Early signs therefore appear promising but obviously more research is required to confirm this idea. Our studies in animals have revealed that by restricting vitamin D intake in pregnant rats, newborns have brains that develop differently. Most notably lateral ventricle volume is increased, a key anatomical finding in patients with schizophrenia. When these animals become adults the increase in lateral ventricles persists. Also when we explore the behaviour of these animals we find a deficit in learning and memory similar to that seen in many schizophrenic patients. Furthermore when we expose these animals to agents that induce psychosis or agents that block psychosis in patients we see a heightened sensitivity in animals that were deprived of this vitamin in utero particularly in locomotion. These behavioural findings are consistent with the best animal models for schizophrenia. At a mechanistic level they indicate an abnormality in the two major neurotransmitters in the brain that have been consistently linked with this disease, dopamine and glutamate. The experiments outlined in this application will attempt to establish the neurochemical basis for these altered behaviours.Read moreRead less
Social Behaviour In Rats Developmentally Deficient In Vitamin D: Modelling The Negative Symptoms Of Schizophrenia
Funder
National Health and Medical Research Council
Funding Amount
$360,927.00
Summary
We are exploring low maternal vitamin D as a biological explanation for a 7-10% increase in the incidence of patients born with schizophrenia in the colder months of the year world wide. Developmental vitamin D (DVD) deficiency in rats leads to long term changes in brain development and behaviour. The aim of this research is to examine social behaviour in DVD deficient rats as a model of negative symptoms of schizophrenia and establish the neurochemical basis for this altered behaviour
Plasticity In The Thalamic Reticular Nucleus During Normal And Altered Postnatal Development
Funder
National Health and Medical Research Council
Funding Amount
$392,036.00
Summary
Thalamic centres concerned with vision send information through the thalamic reticular nucleus to multiple cortical areas in which different aspects of the visual world are analysed. These cortical areas in turn send connections back through the reticular nucleus to the thalamus. Cortical function ultimately depends on the correct connections being established between the sensory receptors and the thalamus and between the thalamus and cortex. Far from being merely a relay station of peripheral s ....Thalamic centres concerned with vision send information through the thalamic reticular nucleus to multiple cortical areas in which different aspects of the visual world are analysed. These cortical areas in turn send connections back through the reticular nucleus to the thalamus. Cortical function ultimately depends on the correct connections being established between the sensory receptors and the thalamus and between the thalamus and cortex. Far from being merely a relay station of peripheral sensory information the dorsal thalamus modifies and interacts with the flow of information around the brain. The reticular nucleus forms an integral part of this information flow. How these connections develop and are modified by disturbance to the visual pathway is crucial to our understanding of brain function. To this end, we will study the connections between three areas of the brain concerned with vision, the thalamic reticular nucleus, the thalamus and the visual cortices. We will focus our study on the development of the reticular nucleus and the importance of a normal visual environment in establishing the proper connections between different brain areas. The importance of studying normal and abnormal development is that it can provide a description of the kinds of experience leading to specific types of neural abnormalites. This information tells us the degree to which connections are malleable and is of potential clinical importance.Read moreRead less
Genetic Adaptations Of Mycobacterium Tuberculosis For Intracellular Survival
Funder
National Health and Medical Research Council
Funding Amount
$187,677.00
Summary
Tuberculosis (TB) remains a significant global public health problem and new approaches to its treatment and prevention are urgently needed. The disease is caused by infection with Mycobacterium tuberculosis, a slow growing organism that lives within cells. How it adapts to survive in this intracellular environment is unknown. Recently the complete genome of M. tuberculosis was sequenced and new techniques developed for manipulating its genes. We plan to use these techniques to identify genes th ....Tuberculosis (TB) remains a significant global public health problem and new approaches to its treatment and prevention are urgently needed. The disease is caused by infection with Mycobacterium tuberculosis, a slow growing organism that lives within cells. How it adapts to survive in this intracellular environment is unknown. Recently the complete genome of M. tuberculosis was sequenced and new techniques developed for manipulating its genes. We plan to use these techniques to identify genes that are more active within the cells. Genes are controlled by short sequences of preceding DNA called promoters. If these promoters are randomly placed in front of readily identifiable reporter genes and inserted into a suitable host strain, it is possible to select for those promoters expressed only inside cells and then identify the promoter and its gene by sequence analysis. We plan to use two types of reporter genes. First, we shall place the M. tuberculosis DNA containing promoters before the gene for a naturally fluorescent protein within the M. bovis BCG host strain and then infect macrophages. If the promoters are switched on inside the cell, the macrophages will become green and can be selected and the promoter identified. After several rounds of selection the promoter is isolated and identified. Second, we shall select the promoters by their ability to produce a protein that is on the surface of the bacterium. We will use these intracellular genes to make better vaccines against TB. Genes that enhance intracellular survival may contribute to the virulence of the TB organism. By removing these genes we can make an attenuated organism suitable as a vaccine. We will test for reduced virulence by growth inside cells in mice. We will also use the intracellular promoter to improve the current BCG vaccine. Proteins expressed inside the cell may also be targets for new TB drugs.Read moreRead less
Physiological Effects Of Manipulating AMPK Signalling Genes
Funder
National Health and Medical Research Council
Funding Amount
$377,250.00
Summary
The AMP activated protein kinase is a metabolic stress sensing protein kinase responsible for matching the supply of energy to the body's functions. During exercise it senses metabolic stress (reduction in energy) caused by muscle contraction and switches on metabolic processes to restore energy. This includes stimulating glucose uptake and burning fat. With training the AMP activated protein kinase also controls genes to adapt the body to future exercise. Reducing caloric intake activates the A ....The AMP activated protein kinase is a metabolic stress sensing protein kinase responsible for matching the supply of energy to the body's functions. During exercise it senses metabolic stress (reduction in energy) caused by muscle contraction and switches on metabolic processes to restore energy. This includes stimulating glucose uptake and burning fat. With training the AMP activated protein kinase also controls genes to adapt the body to future exercise. Reducing caloric intake activates the AMP activated protein kinase to suppress energy consuming activities and modify the expression of genes. This enzyme is a powerful regulator of lipid metabolism, inhibiting both cholesterol and triglyceride synthesis. Many conditions that activate the AMP activated protein kinase (exercise, reduced caloric intake) are associated with a healthy lifestyle, increased longevity and resistance to age onset diseases including cardiovascular disease (atherosclerosis, hypertension), obesity, neurodegeneration and diabetes. It has been found that metformin and rosiglitizone, major drugs used to treat people with type II diabetes activate the AMP activated protein kinase. By manipulating the genes for the AMP-activated protein kinase in mice we expect to gain new insights into the physiological roles of this enzyme and how it functions to protect the body from age onset diseases.Read moreRead less
CD164: A Sialomucin Adhesion Molecule With Potent Growth Inhibitory Properties
Funder
National Health and Medical Research Council
Funding Amount
$242,545.00
Summary
Blood cell production in the adult mammal is normally restricted to the bone marrow. The ongoing production of blood cells is well regulated and dependent on the controlled proliferation and development of rare, multipotent precursors cells commonly termed stem cells. The blood forming stem cells exist in intimate contact with other cells and tissues that comprise the red bone marrow tissue. It is currently thought that stem cell localisation, survival and growth within the bone marrow is, in pa ....Blood cell production in the adult mammal is normally restricted to the bone marrow. The ongoing production of blood cells is well regulated and dependent on the controlled proliferation and development of rare, multipotent precursors cells commonly termed stem cells. The blood forming stem cells exist in intimate contact with other cells and tissues that comprise the red bone marrow tissue. It is currently thought that stem cell localisation, survival and growth within the bone marrow is, in part, regulated by specific interactions between the stem cells and neighbouring cells or the biochemical products of these cells. Stem cells use specific cell surface structures or cell adhesion molecules to mediate these important interactions. This project seeks to investigate the role in blood cell production, of a specific cell surface molecule, CD164, a member of a larger family of molecules with similar structural features thought to be involved in inhibition of cell growth. The main focus of the project is to identify a ligand or binding molecule for CD164. This information will allow an investigation of the consequences of binding between CD164 and its ligand by stem cells. It is proposed that the CD164-ligand interaction is one of a number of important inhibitory interactions used to regulate proliferation of stem cells. These studies will be greatly facilitated by the generation of a mouse lacking CD164.Read moreRead less
The Role Of The Suppressors Of Cytokine Signalling 6 And 7 In Cerebral Cortex Development
Funder
National Health and Medical Research Council
Funding Amount
$377,189.00
Summary
Defects in neuronal cell migration during embryonic development lead to mental retardation and epilepsy. Although neuronal migration is essential for the development of normal intelligence, we know relatively little about the molecular mechanisms that regulate this process. We have identified two proteins, Socs6 and Socs7, which are essential for neuronal migration and normal cerebral cortex development. We propose to fully investigate the function of Socs6 and Socs7 during cortex development.
The Role Of The Ras Signalling Molecule, C3G, In The Interaction Of Neural Precursor Cells And Their Environment
Funder
National Health and Medical Research Council
Funding Amount
$319,446.00
Summary
Developmental brain disorders affect 1-3% of the population. The mental retardation disease spectrum includes neuronal migration disorders and neural precursor proliferation disorders. We propose to study a molecular mechanism regulating neuronal migration, survival and proliferation. We have identified a protein, C3G, which is essential for three aspects of nervous system development: (A) C3G limits neural precursor cell proliferation. (B) C3G is essential for neuronal survival. (C) C3G is cruc ....Developmental brain disorders affect 1-3% of the population. The mental retardation disease spectrum includes neuronal migration disorders and neural precursor proliferation disorders. We propose to study a molecular mechanism regulating neuronal migration, survival and proliferation. We have identified a protein, C3G, which is essential for three aspects of nervous system development: (A) C3G limits neural precursor cell proliferation. (B) C3G is essential for neuronal survival. (C) C3G is crucial for neuronal migration. C3G acts in a cascade of proteins, known as the Ras signalling pathway, which transmits signals from the extracellular environment into the cell nucleus to elicit appropriate responses of the cell to cues from the outside. We will identify proteins that, together with C3G, affect the important processes of neural precursor proliferation, and neuron survival and migration. This project will fully characterise a key regulatory mechanism of cellular processes crucial to the development of normal intelligence.Read moreRead less
Mechanisms Controlling Interneuron Migration And Layering In The Cortex
Funder
National Health and Medical Research Council
Funding Amount
$613,060.00
Summary
This work will increase our understanding of how the brain is assembled and what mechanisms control this process. Understanding this highly orchestrated string of events is vital as abnormal positioning and numbers of neurons are known pathologies in brains of patients with epilepsy and schizophrenia. Using state of the art equipment we can visualize neurons moving in brain slices in real-time and investigate environmental factors involved in this important process.