The Role Of UPF3B And Nonsense Mediated MRNA Decay Surveillance In The Pathology Of Intellectual Disability.
Funder
National Health and Medical Research Council
Funding Amount
$789,954.00
Summary
Proper functioning of the nonsense mediated mRNA decay (NMD or 'mRNA police') is crucial for any cell to ensure normal development and function. When NMD is compromised the outcome is learning and memory problems, autism or schizophrenia. Under this project we study malfunctioning NMD using stem and neuronal cells derived from patients' skin cells. Some of the affected genes might be considered for therapeutic interventions. NMD is relevant to 1000s of human disorders and as such it is of fundam ....Proper functioning of the nonsense mediated mRNA decay (NMD or 'mRNA police') is crucial for any cell to ensure normal development and function. When NMD is compromised the outcome is learning and memory problems, autism or schizophrenia. Under this project we study malfunctioning NMD using stem and neuronal cells derived from patients' skin cells. Some of the affected genes might be considered for therapeutic interventions. NMD is relevant to 1000s of human disorders and as such it is of fundamental importance.Read moreRead less
The Role Of The Mammalian Grainyhead-like Gene Family In Neural Tube Closure
Funder
National Health and Medical Research Council
Funding Amount
$635,547.00
Summary
Failure of the skin to close over the brain and spinal cord during human development results in the devastating congenital birth defects anencephaly and spina bifida, known collectively as the neural tube defects. These are the second most common congenital birth defects affecting 1:1000 pregnancies. Our laboratories have identified a family of genes essential for the closure of the neural tube in mammals. The aim of this proposal is to understand the mechanisms of action of these genes with a v ....Failure of the skin to close over the brain and spinal cord during human development results in the devastating congenital birth defects anencephaly and spina bifida, known collectively as the neural tube defects. These are the second most common congenital birth defects affecting 1:1000 pregnancies. Our laboratories have identified a family of genes essential for the closure of the neural tube in mammals. The aim of this proposal is to understand the mechanisms of action of these genes with a view to developing new preventative therapeutics.Read moreRead less
Benchmarking the neurophysiology of human cortex models in vitro. This project aims to improve human brain models in vitro by developing an analytical tool benchmarking biophysical similarities to the adult human cortex. This project expects to generate new knowledge by testing for the first time the theory that integrating sensory-like inputs and awake/sleep-like cycles of electrical activity in vitro may complete the maturation of human brain organoid models. It will also generate new methods ....Benchmarking the neurophysiology of human cortex models in vitro. This project aims to improve human brain models in vitro by developing an analytical tool benchmarking biophysical similarities to the adult human cortex. This project expects to generate new knowledge by testing for the first time the theory that integrating sensory-like inputs and awake/sleep-like cycles of electrical activity in vitro may complete the maturation of human brain organoid models. It will also generate new methods to simplify the analysis of multimodal path-clamping data (Patch-seq). Expected outcomes will facilitate research collaboration and the reproducibility of accurate experimental replicates of the human brain. This will provide significant benefits in the global race to understand human brain computation mechanisms.Read moreRead less
A Zebrafish Model Of Facioscapulohumeral Dystrophy For Therapy Development And Functional Studies
Funder
National Health and Medical Research Council
Funding Amount
$390,601.00
Summary
This project seeks to develop a zebrafish model for a genetic muscle-wasting disease called facioscapulohumeral dystrophy (FSHD). Our zebrafish model will enable us to better understand the biological mechanisms underlying the disease, as well as provide a platform for therapeutic testing and discovery.
Uncovering The Function Of Susceptibility Variants In Alzheimer's Disease: From GWAS To Cell-Type Specific EQTLs And MQTLs
Funder
National Health and Medical Research Council
Funding Amount
$647,804.00
Summary
This project will investigate some of the genetic and epigenetic changes that occur inside certain brain cells that make them selectively vulnerable to Alzheimer's disease, in order to better understand the mechsnisms that give origin to the disease and identify possible targets for precision therapies.
The Molecular Basis For Target Selection In The Central Nervous System By Sensory Axons
Funder
National Health and Medical Research Council
Funding Amount
$251,325.00
Summary
The normal function of the brain depends upon the specific connections that nerve cells make with each other. These connections are set up in the developing embryo when nerve cells send out long processes - axons - which grow towards their synaptic targets. How axons select their correct targets from amongst the millions of alternatives in the developing brain is unknown. A better understanding of this problem will help us develop therapies to assist regenerating axons re-establish correct conne ....The normal function of the brain depends upon the specific connections that nerve cells make with each other. These connections are set up in the developing embryo when nerve cells send out long processes - axons - which grow towards their synaptic targets. How axons select their correct targets from amongst the millions of alternatives in the developing brain is unknown. A better understanding of this problem will help us develop therapies to assist regenerating axons re-establish correct connections following injury to the brain or spinal cord. We propose to use a simple model system, the embryo of the fruitfly Drosophila, to find molecules that are involved in this process of neuron target recognition - ' axon targeting' molecules - and to study how they work. Drosophila can be genetically manipulated in ways not possible in higher animals. Furthermore the simplicity of its nervous system means that we can determine the connections of individual nerve cells with a high degree of precision. In the first part of our project, we will examine Drosophila embryos that carry mutations in genes suspected to code for targeting molecules. We will stain individual sensory nerve cells in these embryos with dyes to reveal the anatomy of their axons in the brain. If sensory axons terminate abnormally in the brain of a given mutant, the affected gene is likely to code for an axon targeting molecule. In the second part of the study, we will investigate the functions of candidate axon targeting molecules using two approaches. Firstly, we will seek to determine whether the molecule acts in the sensory axons or in their target cells. Secondly, we will use time-lapse microscopy to study how the homing behaviour of the sensory axons is affected in mutant embryos. The results of these studies will lead us closer to an answer to the question: How do axons recognise their specific target cells in the brain?Read moreRead less
The Role Of Cell Adhesion Molecules In Regulation Of Axon Advance
Funder
National Health and Medical Research Council
Funding Amount
$426,006.00
Summary
All cells contain on their surface a class of molecules, cell adhesion molecules, that enable them to adhere to other cells in tissues. Cell adhesion molecules have long been known to be involved in the guidance of axons to their targets during development. However the molecular mechanisms by which these molecules act are largely unknown. We propose to use the powerful genetic tools available in the fruitfly to dissect the mechanisms by which two cell adhesion molecules promote axon growth.