Glutathione is a natural antioxidant, which is known to protect cells in the body from chemical damage. A small part of the glutathione in cells is found in the mitochondria, a structure that is involved in producing the chemical energy needed for normal cell function. The mitochondria are also involved under some circumstances in promoting the death of cells. Although glutathione in general has been well studied, much less attention has been paid to the function of glutathione in mitochondria, ....Glutathione is a natural antioxidant, which is known to protect cells in the body from chemical damage. A small part of the glutathione in cells is found in the mitochondria, a structure that is involved in producing the chemical energy needed for normal cell function. The mitochondria are also involved under some circumstances in promoting the death of cells. Although glutathione in general has been well studied, much less attention has been paid to the function of glutathione in mitochondria, particularly in cells from the brain. Our recent studies indicate that this mitochondrial pool of glutathione is particularly important in limiting the death of cells from the brain when exposed to damaging substances that are increased in some diseases. Thus, the capacity of mitochondrial glutathione to deal with such substances might be a factor in determining the extent of cell loss in the brain, which is an important determinant of symptoms in some of the major neurological diseases. Consistent with this possibility, we have obtained evidence indicating that decreases in glutathione in the mitochondria contribute to the cell death and brain damage that results from a stroke. In our proposed studies, we will investigate the function of mitochondrial glutathione in the two major cell populations from the brain, neurons and astrocytes. We will characterise the protective role of the glutathione and investigate how it enters the mitochondria and what factors influence the amount that is present. This will provide new insights into the function of glutathione in the mitochondria and could also suggest novel approaches for manipulating this antioxidant pool. We will also study models of stroke and some related brain disorders to more directly test the role of this antioxidant in disease and to assess whether manipulating the content of glutathione in the mitochondria has the potential to reduce damage and improve function in these disordersRead moreRead less
Alzheimer's Disease And Related Disorders: Mechanism Of Tau Pathology In Established And Novel Transgenic Animal Models
Funder
National Health and Medical Research Council
Funding Amount
$423,017.00
Summary
Alzheimer's disease (AD) is a devastating neurodegenerative disease for which no cure is available. It affects more than 15 million people worldwide. There are estimates that by 2040, approximately 500'000 Australians will suffer from AD, with associated health costs of about 3% of the GDP. AD is characterized by two major brain lesions, beta-amyloid plaques and neurofibrillary tangles (NFTs). The latter contain a protein called tau which is in a fibrillar and highly phosphorylated state. We wer ....Alzheimer's disease (AD) is a devastating neurodegenerative disease for which no cure is available. It affects more than 15 million people worldwide. There are estimates that by 2040, approximately 500'000 Australians will suffer from AD, with associated health costs of about 3% of the GDP. AD is characterized by two major brain lesions, beta-amyloid plaques and neurofibrillary tangles (NFTs). The latter contain a protein called tau which is in a fibrillar and highly phosphorylated state. We were the first to establish a transgenic animal model of pre-tangles and, together with Dr. Hutton's laboratory, of NFT formation. We could further show that injections of beta-amyloid into brains of our tau mutant mice enhanced the NFT pathology in these mice. By Functional Genomics we identied genes and proteins, which are induced by tau expression. The specific aim of this proposal is to determine whether oxidative stress enhances the tau pathology in our tau mutant mice and whether distinct brain areas are particularly susceptible to this kind of stress. The reason for addressing this question is twofold: On the one hand, we have found in our mice that reactive oxygen species are increased, secondly it is known that some brain areas in the AD brain are degenerating, whereas others are not. A second aim is to develop novel tau transgenic models where individual interactions of tau with cellular proteins are disturbed. Finally, we want to determine whether the two kinases BMX and FAK and the phosphatase PPV regulate tau phosphorylation in vivo. Together, we hope that our efforts lead to a better understanding of the pathogenic mechanisms in AD and related disorders. As pathocascades are likely to be shared between a range of diseases, these findings may also contribute to other fields of research, such as Parkinson's disease. Ultimately, these efforts will assist in the development of a safe treatment of AD.Read moreRead less
Targeting Necroptosis Signalling To Counter Stroke-induced Brain Injury
Funder
National Health and Medical Research Council
Funding Amount
$605,809.00
Summary
The origins of the brain injury that arises from stroke remain a matter of enormous interest. Our work suggests that a poorly understood form of cell death, termed necroptosis, contributes to injury to the brain following stroke. In addition to developing an advanced understanding of this process, we will use drugs developed at the Walter and Eliza Hall Institute to test whether blocking this process might be a plausible therapeutic strategy in stroke patients.
Mechanism Of Action Of A Quinazolinone In Models Of PD
Funder
National Health and Medical Research Council
Funding Amount
$667,548.00
Summary
By the time symptoms of Parkinson's disease (PD) appear, 60-70% of the cells in a crucial part of the brain called the substantia nigra have been destroyed and within a few years of diagnosis, most of the remaining cells have died. This project investigates the causes of this cell loss and a how a new class of compounds could interrupts the process. Success in achieving the aims of this proposal will add to our knowledge of the causes of neuronal death in PD
Subcellular recruitment of a RhoA ubiquitination complex by Rnd proteins. This study addresses a novel molecular mechanism through which members of the Rnd family of GTP-binding proteins regulate the morphology and migration of immature nerve cells of the developing nervous system. This study has broad implications for the understanding of cell migration during embryo development, as well as in health and disease.
Enhancing neurogenesis in the adult primate brain. New neurons are robustly generated in the subependymal zone (SEZ) during human development. Thus, the SEZ may represent an endogenous modifiable source of neurons to enhance plasticity and therapeutic potential in the brain. However, despite our preliminary data, SEZ neurogenesis beyond the first months of life is controversial. This project aims to understand changes in the capacity for human SEZ proliferation from birth through to ageing and w ....Enhancing neurogenesis in the adult primate brain. New neurons are robustly generated in the subependymal zone (SEZ) during human development. Thus, the SEZ may represent an endogenous modifiable source of neurons to enhance plasticity and therapeutic potential in the brain. However, despite our preliminary data, SEZ neurogenesis beyond the first months of life is controversial. This project aims to understand changes in the capacity for human SEZ proliferation from birth through to ageing and whether neurogenesis may be induced by inflammation in the adult. Using transcriptomics we will also determine how the neurogenic environment changes with age/inflammation. This project is an important step in proving that the brain's potential to generate new neurons extends beyond infancy.Read moreRead less
Cell Death In The Retina: Analysing The Switch That Triggers Dependency On Target-derived Trophic Factors
Funder
National Health and Medical Research Council
Funding Amount
$428,414.00
Summary
Construction of the developing nervous system in the embryo involves the creation of nerve cells and their connections, but also involves loss of a proportion of these cells prior to maturation. We will study this process of cell death and how developing nerve cells switch on their dependency to survival factors. In so doing we will better understand what happens when brain development goes wrong and also devise new ways to protect nerve cells in the injured or degenerate adult nervous system.
Modelling human brain development with stem cells and biomaterials. With limited resources to directly study and advance our understanding of human neural development, this
proposal will establish models of 4 key stages. Employing innovative, interdisciplinary approaches, biomaterials will be fabricated to provide structural and chemical support for human stem cells during: (i) neural induction, (ii) specification into neuronal progenitor subpopulations, (iii) neuronal maturation and integration ....Modelling human brain development with stem cells and biomaterials. With limited resources to directly study and advance our understanding of human neural development, this
proposal will establish models of 4 key stages. Employing innovative, interdisciplinary approaches, biomaterials will be fabricated to provide structural and chemical support for human stem cells during: (i) neural induction, (ii) specification into neuronal progenitor subpopulations, (iii) neuronal maturation and integration into complex neural networks as well as, (iv) the organisation of neurons into larger 3-dimensional brain structures, namely folding of the human cortex. Further, biomaterials developed here have commercialisation potential, targeted at standardizing the culturing of human stem cells to defined neural populations.
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Compromised Fetal Brain Development: Neurogenesis And The Potential For Therapeutic Intervention.
Funder
National Health and Medical Research Council
Funding Amount
$497,280.00
Summary
Lack of oxygen to the fetal brain during pregnancy is thought to be the main causes of brain injury in newborns. Some of these infants will suffer developmental and behavioural problems including cerebral palsy, schizophrenia and epilepsy. Currently, there is no effective treatment to redress these changes in brain development and this is one of the major challenges in perinatal medicine today. We have previously shown in a guinea pig model of chronic placental insufficiency (reduced oxygen and ....Lack of oxygen to the fetal brain during pregnancy is thought to be the main causes of brain injury in newborns. Some of these infants will suffer developmental and behavioural problems including cerebral palsy, schizophrenia and epilepsy. Currently, there is no effective treatment to redress these changes in brain development and this is one of the major challenges in perinatal medicine today. We have previously shown in a guinea pig model of chronic placental insufficiency (reduced oxygen and nutrient levels during pregnancy) that there is a reduction in neurons and in the connections between them. This may result from a reduction in number of newly generated neurons (neurogenesis), or an increase in neuronal death (apoptosis), or both. To develop therapeutic strategies to improve brain growth and ultimately functional recovery, we must understand the mechanisms which lead to these brain changes. In this project, we will use our guinea pig model to: 1) determine whether a suboptimal fetal environment decreases neuronal numbers by influencing neurogenesis, apoptosis or both, 2) study changes in the compromised brain environment which are likely to influence apoptosis and neurogenesis, 3) determine whether a suboptimal fetal environment has long-term effects on adult neurogenesis and 4) determine whether treatment with erythropoietin (Epo), a naturally occurring hormone, can resolve deficits in brain development and function. Epo is an exciting candidate as it is, or is in the process of being used to treat stroke and newborn asphyxiation. Epo has also been shown to prevent neuronal death and promote neurogenesis following brain injury. Understanding the mechanisms and finding effective treatments for brain damage is a vital area of endeavour if we are to help infants develop their maximum potential and reduce the enormous social, economic and educational burden which must be borne by the individual and society in general when things go wrong during pregnancy.Read moreRead less
Modelling the human nervous system with human pluripotent stem cells. The human nervous system is one of the most complex structures evolved to date. In order to understand how it functions, and dysfunctions in a diseased state, it is fundamental to decipher how it develops to generate various neuronal populations that form this elaborate network. Human stem cells provide a valuable source to study such processes. The aim of this project is to use human stem cells to study how early progenitor c ....Modelling the human nervous system with human pluripotent stem cells. The human nervous system is one of the most complex structures evolved to date. In order to understand how it functions, and dysfunctions in a diseased state, it is fundamental to decipher how it develops to generate various neuronal populations that form this elaborate network. Human stem cells provide a valuable source to study such processes. The aim of this project is to use human stem cells to study how early progenitor cell types that structure the nervous system are generated and how their neuronal derivatives form connectivity and functional synapses. The outcome of these studies is that we will establish a cellular model of human neurogenesis that can be utilised to study developmental disease processes.Read moreRead less