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
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.
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
Emerging Infectious Neurological Diseases In Australia; From Enhanced Recognition To Improved Response
Funder
National Health and Medical Research Council
Funding Amount
$189,384.00
Summary
Infectious neurological diseases(IND) such as encephalitis are severe and frequently cause long term disability. New IND like Zika pose a real threat. During his PhD, Dr Britton identified outbreaks of encephalitis in children and described serious consequences. Here, Dr Britton proposes to extend his work across all ages, include other types of IND and explore novel methods to detect outbreaks. He will work with experts at leading national research centres in surveillance and infectious disease
Blood-brain Barrier And White Matter Damage In The Immature Rat Brain Following Systemic Inflammation
Funder
National Health and Medical Research Council
Funding Amount
$353,173.00
Summary
Clinical obstetric and paediatric studies have identified an association between intrauterine infection occurring around two thirds of the way through pregnancy, premature birth and a specific form of damage to the brain of the newborn. This damage mainly affects white matter tracts. These tracts are aggregations of nerve fibres that make the connections between different parts of the brain and may result in cerebral palsy or other neurological disorders. The association between maternal infecti ....Clinical obstetric and paediatric studies have identified an association between intrauterine infection occurring around two thirds of the way through pregnancy, premature birth and a specific form of damage to the brain of the newborn. This damage mainly affects white matter tracts. These tracts are aggregations of nerve fibres that make the connections between different parts of the brain and may result in cerebral palsy or other neurological disorders. The association between maternal infection and brain damage, one form of which is cerebral palsy, is well established from clinical epidemiological studies, but the biological mechanism of this link is unknown. The CIs' group has recently shown that the condition can be reproduced in neonatal rats at a stage of brain development in the rat that is equivalent to the critical time in human brain development when infection may be associated with brain damage. The CIs' group has shown that an induced inflammatory state similar to a bacterial infection, results in damage to blood vessels in the white matter and is associated with changes in white matter, as occurs in affected babies. The purpose of this study is to understand the nature of the damage to white matter blood vessels and the mechanisms by which materials in blood, which in the normal brain do not pass from the blood to the brain across the blood-brain barrier, are able to do so via the inflammation damaged blood vessels. The study also aims to show whether it is components of the blood entering the brain via the damaged blood vessels that are responsible for the damage to white matter in the immature brain. The outcome should lead to development of ways to improve clinical care of women who acquire infections during pregnancy.Read moreRead less