Identification Of Novel Regulatory Factors In Midbrain Development To Improve Cell Therapies For The Treatment Of Parkinson’s Disease
Funder
National Health and Medical Research Council
Funding Amount
$311,860.00
Summary
Cell transplantation is one of the most promising therapeutic strategies for the treatment of Parkinson’s disease. Cells are transplanted directly into the brain of the patient and can compensate for those lost to the disease. In this project we are identifying new genes that regulate the normal development of the transplanted cells in mice. We hope to use this knowledge to improve the reliability and effectiveness of the approach, bringing the therapy closer to the clinic.
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.
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.
How Are Axons Guided To Their Targets In The Developing Nervous System?
Funder
National Health and Medical Research Council
Funding Amount
$329,644.00
Summary
Many neurodevelopmental disorders are probably the result of wiring defects. In this project we will use new technologies to study how growing nerve fibres are steered to their targets during development, and use this data to create new mathematical models which can predict which way nerve fibres should grow in different situations. This will advance our understanding of the mechanisms underlying both normal and abnormal brain development.
The Role Of Netrin-DCC In The Development Of The Corpus Callosum
Funder
National Health and Medical Research Council
Funding Amount
$512,065.00
Summary
During embryonic development neurons send out axons that connect to other target neurons within the brain. The proper connectivity of these axons is vital to brain function. The largest axon tract in the brain is called the corpus callosum and connects neurons in the left and right cerebral hemispheres. When the corpus callosum does not form, significant cognitive, motor and sensory deficits occur in patients. This condition, known as agenesis of the corpus callosum (ACC), is associated with ove ....During embryonic development neurons send out axons that connect to other target neurons within the brain. The proper connectivity of these axons is vital to brain function. The largest axon tract in the brain is called the corpus callosum and connects neurons in the left and right cerebral hemispheres. When the corpus callosum does not form, significant cognitive, motor and sensory deficits occur in patients. This condition, known as agenesis of the corpus callosum (ACC), is associated with over 50 different human congenital syndromes. Thus understanding how the genes and molecules involved in the formation of the corpus callosum function in normal development can provide the basis for our understanding of what goes wrong in ACC. In this proposal we will investigate the role of the axon guidance molecule Netrin1, and its receptor DCC, in development of the corpus callosum in both a mouse model and in humans with malformations of the corpus callosum. Although Netrin1-DCC signalling has traditionally been associated with mechanisms of axon guidance, we hypothesize that these molecules may play a different role, specifically in cellular adhesion and ultimately in the fusion of the two cerebral hemispheres, in a manner that allows the corpus callosum to form. A second role for Netrin1-DCC signalling may be in the guidance of these axons once the midline has fused correctly and we investigate this in Aim 2 of the proposal. Finally, we are collaborating with a paediatric neurologist at UCSF, who has identified several mutations in the DCC gene in patients with ACC. In Aim 3 we test whether these mutations disrupt the function of DCC in callosal axon pathfinding. Understanding how these genes function during development of the brain and how their function may be altered in ACC is crucial to providing a proper diagnosis and prognosis for these patients. Ultimately, understanding more about how these genes function could also lead to prevention of these disorders.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
Enhancement Of Newborn Neuron Survival To Promote Repair Following Adult Brain Injury
Funder
National Health and Medical Research Council
Funding Amount
$555,780.00
Summary
Following brain damage tissue needs to be rebuilt and newborn nerve cells need to survive. Identification of factors that enhance the numbers and promote the survival and appropriate integration of newborn nerve cells is therefore important and over the last few years we have identified two regulatory factors that are prime candidates to enhance numbers and survival of newborn neurons following injury: the Rho pathway and suppressor of cytokine signalling-2, which we will test for effectiveness ....Following brain damage tissue needs to be rebuilt and newborn nerve cells need to survive. Identification of factors that enhance the numbers and promote the survival and appropriate integration of newborn nerve cells is therefore important and over the last few years we have identified two regulatory factors that are prime candidates to enhance numbers and survival of newborn neurons following injury: the Rho pathway and suppressor of cytokine signalling-2, which we will test for effectiveness following brain injury.Read moreRead less
Sez-6 Signalling Mechanisms And Function In The Developing Neocortex
Funder
National Health and Medical Research Council
Funding Amount
$501,815.00
Summary
Over the course of evolution, the mammalian brain cortex has become disproportionately large with respect to other brain regions. The dramatic increase in processing power resulting from the increased neuronal number and connectivity in the cortex has enabled us to acquire functions that make us human, such as the use of language. In spite of the enormous difference in size between the brains of humans and those of mice, studies on cortical development in mice are relevant to humans since the or ....Over the course of evolution, the mammalian brain cortex has become disproportionately large with respect to other brain regions. The dramatic increase in processing power resulting from the increased neuronal number and connectivity in the cortex has enabled us to acquire functions that make us human, such as the use of language. In spite of the enormous difference in size between the brains of humans and those of mice, studies on cortical development in mice are relevant to humans since the organization of the cortex (thickness, layer patterning and regional specialization) is very similar in these two organisms, and indeed, in all mammals. A complex series of developmental events is required to produce a normal brain cortex. Malformations in the cortex occurring in human neurological disorders, including epilepsy and mental retardation, result from mutations in genes regulating crucial developmental processes. Failure of developing nerve cells to make the correct connections can result in these, or other, debilitating neurological conditions. We have evidence that a brain protein called Seizure-related gene 6 (Sez-6) regulates normal connectivity and function of neurons in the mature cortex. We will determine the molecular pathways used for signalling of Sez-6 and also investigate in detail the formation of connections between cortical neurons early in development and how these connections become aberrant in the absence of Sez-6 function.Read moreRead less
Role Of Chemokines And Interferons In Neural Progenitor Cell Function
Funder
National Health and Medical Research Council
Funding Amount
$521,178.00
Summary
Regeneration of the central nervous system following disease or injury is extremely limited and frequently results in substantial impairment. A potential therapy to replace damaged or killed nervous system cells is the use of neural stem cells. Neural stem cells are present in the central nervous system and frequently attempt, but fail to repair nervous system damage. This project aims to examine factors that regulate neural stem cell function including factors that may regulate their ability to ....Regeneration of the central nervous system following disease or injury is extremely limited and frequently results in substantial impairment. A potential therapy to replace damaged or killed nervous system cells is the use of neural stem cells. Neural stem cells are present in the central nervous system and frequently attempt, but fail to repair nervous system damage. This project aims to examine factors that regulate neural stem cell function including factors that may regulate their ability to migrate or become appropriate neural cell types. Of particular interest are factors known as chemokines that regulate cell migration as well as have a variety of other effects. In addition, interferons, which are inflammatory molecules present in the damaged nervous system and that we have shown affect neural stem cell function, may interact with chemokines and will also be examined. In addition to examining the effects of these factors on neural stem cells, the signalling pathways they use in these cells will also be determined.Read moreRead less