The Roles Of EZH2 And FOXO1A In CNS-PNET Pathogenesis.
Funder
National Health and Medical Research Council
Funding Amount
$467,517.00
Summary
Although CNS-PNETs are the most common embryonal CNS tumours of childhood and cause significant mortality and morbidity, there is a very limited understanding of the pathogenesis of this aggressive disease. This situation is a major handicap to the development of more specific and effective therapies. While a better understanding of the fundamental pathology of CNS-PNETs will have immediate diagnostic implications, the elucidation of the biochemical pathways that are disrupted in these tumours w ....Although CNS-PNETs are the most common embryonal CNS tumours of childhood and cause significant mortality and morbidity, there is a very limited understanding of the pathogenesis of this aggressive disease. This situation is a major handicap to the development of more specific and effective therapies. While a better understanding of the fundamental pathology of CNS-PNETs will have immediate diagnostic implications, the elucidation of the biochemical pathways that are disrupted in these tumours will facilitate the design of new drugs that are specifically directed towards the critical proteins in these pathways. The identification of specific genes and-or pathways that are deregulated in CNS-PNET cells is essential for the development of safer, more directed, and more effective therapies that are urgently required for the treatment of those with this devastating disease.Read moreRead less
Cell Type Specification In Developing CNS: Functional Analysis Of Sox14
Funder
National Health and Medical Research Council
Funding Amount
$468,055.00
Summary
The central nervous system (CNS) is the most complex organ in the body. The vast majority of nerve cells in the CNS are classified as 'interneurons'. These cells relay sensory information and motor commands within the CNS. Abnormal functioning of interneurons is likely to be the underlying cause of some, if not many, human nervous system diseases. However, very little is known of the precise anatomy and function of interneurons, which genes control their development, and how these functions are ....The central nervous system (CNS) is the most complex organ in the body. The vast majority of nerve cells in the CNS are classified as 'interneurons'. These cells relay sensory information and motor commands within the CNS. Abnormal functioning of interneurons is likely to be the underlying cause of some, if not many, human nervous system diseases. However, very little is known of the precise anatomy and function of interneurons, which genes control their development, and how these functions are maintained in the adult. This has been largely due to a lack of efficient and reliable methods to identify and study interneurons. We have previously discovered that a gene termed Sox14 is active in distinct interneuron groups in the embryonic brain and spinal cord. Sox14 is a member of the Sox gene family, many of which act as genetic switches to control cell and tissue development. We found that Sox14 has been extremely well conserved throughout evolution and is active in similar interneuron groups in a number of animal species. These studies led us to hypothesise that Sox14 controls a critical molecular step in the generation of certain interneurons that may be involved in reflexes, locomotion or motor coordination. In this project, we will investigate both the role of Sox14 in interneuron development and the functions of interneurons in which this gene is active. We will do so by combining modern molecular and genetic techniques with physiological approaches. This project will reveal critical molecular steps in CNS development and determine the functions of a specific group of interneurons. To this end, we will generate mouse strains in which a specific group of interneurons are genetically marked and can be manipulated during development. We envisage that these mice with 'modified brain circuits' will become unique resources for future investigations of selected interneuron types and their functions.Read moreRead less
Primary central nervous system (CNS) tumours, arising in the brain and spinal cord, are the leading cause of cancer-related deaths in children less than 15 years of age. Medulloblastomas and other primitive neuroectodermal tumours (PNETs) are the most common form of primary childhood brain tumours, accounting for 25-30% of cases. Despite notable recent advances in our understanding of the molecular genetic basis of malignancies, the pathogenesis of CNS PNETs remains obscure. To address this prob ....Primary central nervous system (CNS) tumours, arising in the brain and spinal cord, are the leading cause of cancer-related deaths in children less than 15 years of age. Medulloblastomas and other primitive neuroectodermal tumours (PNETs) are the most common form of primary childhood brain tumours, accounting for 25-30% of cases. Despite notable recent advances in our understanding of the molecular genetic basis of malignancies, the pathogenesis of CNS PNETs remains obscure. To address this problem, we propose to apply a novel combinatorial approach for the identification of PNET tumour suppressor genes utilising both representational difference analysis (RDA) and microarray expression profiling. Data from this study will help to elucidate the molecular pathways that are compromised in the initiation and growth of PNETs. This information will have direct implications for the development of improved diagnostic and prognostic indicators necessary for the design of more effective therapeutic strategies for the treatment of PNET patients.Read moreRead less
Intraocular Transplantation And Regeneration Of Retinofugal Pathways In Rodents
Funder
National Health and Medical Research Council
Funding Amount
$370,937.00
Summary
In the adult human brain and spinal cord there is little or no intrinsic capacity for replacement of lost or dying neurons, and there is minimal spontaneous repair of nerve fibre pathways. Thus traumatic injuries, stroke, or loss of neurons due to chronic degenerative disease result in functional impairments that are usually severe and long-lasting. The personal, social and economic costs associated with these neurological problems are enormous. New ways must be found of protecting and-or replen ....In the adult human brain and spinal cord there is little or no intrinsic capacity for replacement of lost or dying neurons, and there is minimal spontaneous repair of nerve fibre pathways. Thus traumatic injuries, stroke, or loss of neurons due to chronic degenerative disease result in functional impairments that are usually severe and long-lasting. The personal, social and economic costs associated with these neurological problems are enormous. New ways must be found of protecting and-or replenishing nerve cells in damaged CNS gray matter, and new methods are also required to help reconstruct fibre tracts after injury. Using the visual system as an experimental model, the aims of the proposed work are to develop novel transplantation and surgical strategies to: (i) Incorporate new cells into retinae that have been selectively depleted of endogenous neurons (ii) Promote the effective regeneration of large numbers of adult retinal axons through prosthetic peripheral nerve bridging grafts and into host CNS distal to the injury. The results obtained from the first series of studies will not only be of direct relevance to the future treatment of human retinal degenerative disorders, but will also increase our overall understanding of how best to ensure the differentiation and stable integration of different types of transplanted cells within the compromised host CNS. The second series of experiments should lead to an entirely new approach to nerve pathway reconstruction, relevant to both brain and spinal cord injuries. The ultimate aim of this experimental work is to improve the management and treatment of human CNS injury and disease, leading to better functional recovery and rehabilitation.Read moreRead less
Neurogenic Hypertension In The Spontaneously Hypertensive Mouse : Role Of The Hypothalamic-brainstem Sympathetic Axis
Funder
National Health and Medical Research Council
Funding Amount
$475,917.00
Summary
In human high blood pressure, particularly in the young, an overactive nervous system is thought to be a major underlying cause. Using a unique mouse model of high blood pressure which closely resembles this aspect of the human disease, we will examine which brain cells and neuro- chemicals are involved, particularly in a small area that is involved in regulating the hormonal and nervous system response to stress. From this we hope to be able to target these chemicals with specific therapy.