Cellular Mechanisms Controlling Neural Crest Cell Migration Along The Developing Gut
Funder
National Health and Medical Research Council
Funding Amount
$368,895.00
Summary
Within the wall of the gut, there are a large number of neurons, probably more than are in the spinal cord. These enteric neurons play an essential role in controlling a number of gut functions including peristalsis (the propulsion of contents along the gut). Most of the neurons in the gut, including those in the large intestine, arise from precursors that emigrate from the hindbrain, and then migrate into and along the gastrointestinal tract during development. The colonization of the gut by ne ....Within the wall of the gut, there are a large number of neurons, probably more than are in the spinal cord. These enteric neurons play an essential role in controlling a number of gut functions including peristalsis (the propulsion of contents along the gut). Most of the neurons in the gut, including those in the large intestine, arise from precursors that emigrate from the hindbrain, and then migrate into and along the gastrointestinal tract during development. The colonization of the gut by neuron precursors takes 5 days in mice and 6 weeks in humans. Studies of the mechanisms controlling the migration of neuron precursors along the gut have provided fundamental information about cell migration in general. Genetic studies in humans and mice have identified some of the genes that are necessary for the migration of neuron precursors along the gastrointestinal tract, but for some of the key genes, their precise role is unknown. We have recently developed a method for imaging living neuron precursors migrating through explants of embryonic mouse gut. In the current proposal we will meld imaging and genetic studies to understand how mutations in particular genes lead to migration defects. In particular, how do particular mutations affect the migratory behaviour of enteric neural precursors? We have also previously shown that neuron precursors migrate along the gut in close association with axons. We will examine the nature of these interactions - in particular, who is following whom, and what happens when cell migration and axon growth are uncoupled? These studies, which will investigate a number of critical aspects of the migration of neural precursors into and along the developing gut, are central to understanding how the enteric nervous system is established along the gastrointestinal tract.Read moreRead less
Using Stem Cells And Bioengineered Scaffolds To Promote Regeneration Following Necrotic Brain Injury
Funder
National Health and Medical Research Council
Funding Amount
$710,857.00
Summary
A number of injuries, including stroke, result in tissue loss. Consequently promoting repair will require restoration of tissue structure, replacement cells and a supportive environment to promote integration of these new cells. This study will engineer and develop novel scaffolds that can replace tissue whilst additionally providing physical and chemical support for newly implanted stem cells. This work will be conducted in an animal model of stroke.
Standardising Protocols For The Differentiation And Integration Of Human Pluripotent Stem Cell-derived Neural Transplants In Parkinson's Disease
Funder
National Health and Medical Research Council
Funding Amount
$987,664.00
Summary
Clinical trials have shown that transplanting dopamine neurons (specific nerve cells) into the brain of Parkinson’s disease patients can improve symptoms. Trials use fetal tissue for implantation, which is unsustainable and highly variable. This proposal will examine stem cells as an alternative. We will establish a reliable protocol to instruct human stem cells to become dopamine neurons, develop methods to select these cells and, examine the integration of these transplanted cells in the brain
Knowledge, Identification And Exploitation Of Dopaminergic Axon Guidance Cues Will Improve Cell Replacement Therapy For ParkinsonÍs Disease.
Funder
National Health and Medical Research Council
Funding Amount
$481,797.00
Summary
Many obstacles exist for cell transplantation in ParkinsonÍs Disease; namely poor graft survival, restoration of appropriate circuitry and adequate nerve fiber growth from new cells. Using knowledge of how neural circuits are established during fetal development, we will attempt to recapitulate these events following transplantation. Further, we will identify new and novel cues in regulating the connectivity and growth of these nerve fibers.
Regulation Of Neural Progenitor Cell Self-renewal By The RNA-binding Protein ZFP36L1 During Development And Disease
Funder
National Health and Medical Research Council
Funding Amount
$345,401.00
Summary
The timely differentiation of neural stem cells is critical during development, and the unrestrained proliferation of neural stem cells in the adult can lead to deadly brain cancers such as glioma. At present our understanding of the key molecules that regulate neural stem cell behaviour during these processes remains limited. In this proposal we will investigate the molecular determinants underpinning neural stem cell biology, both within the developing brain, and within glioma.
A Novel Treatment For Ischemic Stroke: Preclinical Assessment In The Nonhuman Primate
Funder
National Health and Medical Research Council
Funding Amount
$762,246.00
Summary
A major source of repair inhibition after brain injury is debris from dying cells, which contains proteins that hinder repair. This project will examine the expression of these proteins in a clinically-relevant model of ischemic stroke and determine if blocking the effect of these proteins neutralises their repair-inhibiting properties. If successful, there is likelihood that this drug, and method of delivery, could be translated into the human for treatment following an ischemic stroke.
The Role Of GRHL-3, A Mammalian Homologue Of Drosophila Grainyhead, In Neural Tube Development
Funder
National Health and Medical Research Council
Funding Amount
$496,500.00
Summary
Spina bifida and anencephaly are two common human congenital malformations that form part of a wide spectrum of mutations known collectively as neural tube defects (NTDs). Patients with the most severe form of spina bifida have a failure of the vertebral column and skin to close over the spinal cord and therefore suffer from limb paralysis and marked bladder and bowel dysfunction. Infants with anencephaly have an open cranial vault and failure of normal brain development and die within the first ....Spina bifida and anencephaly are two common human congenital malformations that form part of a wide spectrum of mutations known collectively as neural tube defects (NTDs). Patients with the most severe form of spina bifida have a failure of the vertebral column and skin to close over the spinal cord and therefore suffer from limb paralysis and marked bladder and bowel dysfunction. Infants with anencephaly have an open cranial vault and failure of normal brain development and die within the first few hours of life. These abnormalities occur frequently (1-1000 live births) and are a direct result of failure of the neural tube to close during embryogenesis. NTDs are influenced by both environmental and genetic factors. The best characterised environmental factor is the dietary supplement folate, which when administered before conception results in a reduction in the incidence of spina bifida. The genetic complexity is evidenced by the array of mouse genetic mutations that give rise to NTDs. One of these mouse mutations, known as Curly tail (ct), has served as the major animal model of human NTDs. This is because the ct mice are resistant to folate administration (like most of the cases of spina bifida currently seen in patients) and because the mice seem to have normal development in virtually all other organ systems. Ironically, the genetic mutation that causes the curly tail phenotype has remained undiscovered for over 50 years. We have now identified the gene mutated in the curly tail mice. This gene is highly conserved in humans suggesting that it will play a similar role in neural tube development in man. The gene, known as GRHL-3, is a descendant of a fly gene critical for development of the nervous system in that organism. The studies we propose here will examine the developmental pathways involved in normal neural tube closure in mice and humans and will impact on our understanding of these devastating congenital malformations.Read moreRead less
Seizures appear unpredictable and greatly affect the quality of all aspects of life for patients with epilepsy and their carers. New advances in complex systems theory suggest that transitions from normal brain activity to seizures are preceded by measurable changes in the brain’s responses to stimuli, known as critical slowing. Measurement of critical slowing will enable prediction of seizures, providing a warning system, and possibly an opportunity to deliver preventative therapies.
The Role Of Meninges In Midbrain Dopamine Development
Funder
National Health and Medical Research Council
Funding Amount
$378,311.00
Summary
Dopamine neurons are important for the control of movement, emotion and cognitive function, and are affected in a number of disorders such as Parkinson’s disease. Instrumental in improving our knowledge of disease etiology and the development of new therapies will be a greater understanding of how these cells are initially born during development. This project examines the role of the brain’s meninges in dopamine development and repair and will identify proteins and signaling pathways involved.