Identification Of Regulatory Protein Interactions On The CRH Promoter
Funder
National Health and Medical Research Council
Funding Amount
$216,600.00
Summary
CRH made in the brain controls our response to stress, and when made by the placenta it controls when birth will occur. Changes to the stress response can have important implications in heart disease, cancer, obesity and many other diseases. 70% of neonatal death is a result of premature birth, and pre-term babies that survive are more likely to have intellectual handicap or cerebral palsy. This research will help us understand CRH production during stress and pregnancy.
Gene-environment Interactions And Synaptic Plasticity In The Developing And Dysfunctional Cerebral Cortex
Funder
National Health and Medical Research Council
Funding Amount
$526,026.00
Summary
The cerebral cortex contains many billions of neurons, which are interconnected by trillions of synapses, to form networks underlying our most complex brain functions. It is only after birth, with environmental stimulation, that diverse brain functions begin to emerge. We are interested in the mechanisms whereby the genetic programme regulating maturation of the cerebral cortex is sculpted by interaction with the environment, as well as ongoing gene-environment interactions and mechanisms of pla ....The cerebral cortex contains many billions of neurons, which are interconnected by trillions of synapses, to form networks underlying our most complex brain functions. It is only after birth, with environmental stimulation, that diverse brain functions begin to emerge. We are interested in the mechanisms whereby the genetic programme regulating maturation of the cerebral cortex is sculpted by interaction with the environment, as well as ongoing gene-environment interactions and mechanisms of plasticity in postnatal brain. Many brain disorders, including schizophrenia, autism, epilepsy, Alzheimer's and Huntington's disease, involve abnormal development or function of the cerebral cortex. Our group has recently demonstrated that onset and progression of Huntington's disease, previously considered the epitome of genetic determinism, can be modulated by environmental factors, suggesting that all brain disorders must involve gene-environment interactions. In this project we are focusing on a specific molecular pathway which processes information from the environment and induces experience-dependent changes in the structure and function of neurons in cerebral cortex. We know that the molecular pathway we are examining has been linked to schizophrenia, a disorder of brain development, and we are attempting to understand how disruption of these molecular pathways can lead to the abnormal brain development and plasticity seen in this disease. We hope to discover neurobiological mechanisms which provide integrative understanding at the level of molecules, networks of neurons, and behaviour, in mouse models of brain disorders with disruption of specific genes, receiving different types of environmental stimulation. Analysing normal mice in this project will also provide new information on mechanisms of plasticity in the healthy cerebral cortex, that may underlie higher brain functions such as learning, which occurs throughout postnatal life, and memory.Read moreRead less
How Do BET Bromodomain Proteins Regulate Gene Expression?
Funder
National Health and Medical Research Council
Funding Amount
$586,791.00
Summary
This project is aimed at defining the biochemical mechanisms of action of a class of gene regulatory proteins (BET proteins) that are currently considered to be exciting drug targets for a range of diseases, predominantly cancer. A better understanding of the means by which BET proteins regulate gene expression will be important for the rational design and application of drugs that selectively target the proteins.
Australian Centre For Vertebrate Mutation Detection (ACVMD)
Funder
National Health and Medical Research Council
Funding Amount
$1,611,794.00
Summary
Over the last 20 years, generation and analysis of genetically modified animals has proven to be an important step in the transition from in vitro studies of gene function to in vivo studies and eventually clinical research. The remarkable parallels between the human, mouse and zebrafish genomes means that there are now many examples of mutations that cause or modify disease in humans, and which lead to similar phenotypes when present in mice and zebrafish. Until recently, the prime method of in ....Over the last 20 years, generation and analysis of genetically modified animals has proven to be an important step in the transition from in vitro studies of gene function to in vivo studies and eventually clinical research. The remarkable parallels between the human, mouse and zebrafish genomes means that there are now many examples of mutations that cause or modify disease in humans, and which lead to similar phenotypes when present in mice and zebrafish. Until recently, the prime method of introducing mutations into specific genes of interest in the mouse (although still unavailable in the fish) was via homologous recombination, and the principal classes of mutations induced were large deletions or insertions. This type of mutation rarely occurs in humans. Rather, point mutations and single-nucleotide polymorphisms are the prevalent form of genetic variation. An alternative approach to the development of mouse models with the more relevant point mutations is TILLING (Targeting Induced Local Lesions IN Genomes). The goal of this Enabling Grant is to make TILLING technology accessible to the Australian research community and in doing so promote movement of research from the in vitro setting into animal models of disease.Read moreRead less
Structural And Functional Studies On RNA Nuclear Retention Mediated By Paraspeckles: A Novel Gene Regulation
Funder
National Health and Medical Research Council
Funding Amount
$290,978.00
Summary
Dynamic interactions between proteins and nucleic acids are essential process in gene regulation, where aberrant regulation leads to various diseases including cancers. The project aims to examine the interactions between paraspeckle proteins and nucleic acid molecules via determination of the structures of protein-nucleic acid complexes at the atomic level. The results will provide a better understanding of a recently discovered gene regulation mechanism and a basis for new gene therapy.
Regulation Of Gene Expression: Biomolecular Interactions In Cellular Development And Disease
Funder
National Health and Medical Research Council
Funding Amount
$2,998,713.00
Summary
This team consists of three of Australia�s younger researchers Merlin Crossley, Joel Mackay and Jacqui Matthews (as Chief Investigators), who are recognized as authorities in the areas of gene regulation and the structural and functional analysis of proteins. They are joined by Mitchell Weiss, a world authority on blood development and clinical disorders,and Alexis Verger, a molecular and cell biologist recruited from France, both as Principal Investigators. Crossley, Mackay and Matthews have wo ....This team consists of three of Australia�s younger researchers Merlin Crossley, Joel Mackay and Jacqui Matthews (as Chief Investigators), who are recognized as authorities in the areas of gene regulation and the structural and functional analysis of proteins. They are joined by Mitchell Weiss, a world authority on blood development and clinical disorders,and Alexis Verger, a molecular and cell biologist recruited from France, both as Principal Investigators. Crossley, Mackay and Matthews have worked as a team for around six years to date, have published together in high-quality international journals, and have received anumber of accolades for their contributions to Australian science. For example, Crossley has won a number of national awards, including the Gottschalk Medal of the Australian Academy of Science; Mackay was recently awarded the Prime Minister�s Prize for Life Scientist of the Year, and Matthews won the only Charles and Sylvia Viertel Medical Research Fellowship to be awarded in 2003. The members of this team have collaborated extensively on the world stage and Crossley, Mackay and Matthews have also taken leadership roles in the Australian scientific community. Mitchell Weiss has been an important collaborator, exchanging reagents and advice, since he and Crossley trained together as postdocs in Stu Orkin�s lab at Harvard in the early 90s. Most recently Weiss, in collaboration with Mackay, has made important discoveries on a-globin production, which has led to several highly significant publications including a seminal paper in Cell in 2004.The program of research put forward in this proposal centres around understanding the mechanisms through which genes are switched on and off, using blood development as a model system, that is also fundamental to human life. The regulation of gene output is essential both during the development of an organism and throughout the course of its life. Problems with this regulation can result in many different disease states, most notably cancer, which includes the many different types of leukemias. At one level, gene output is controlled by networks of specific proteins known as transcription factors that interact both with each other and with DNA. Currently, however, the details surrounding which complexes regulate which genes and the processes that control the making and breaking up of the complexes are not well understood. Knowledge of how these interactions take place will put us in a position to control the output of chosen genes for therapeutic purposes. We propose to use a combination of cell biological, biochemical, and structural approaches to firstly shed light on these complexes and secondly develop reagents that can be used to manipulate the activity of specific genes.Read moreRead less
Elucidation Of The Gene Regulatory Networks That Cause Alzheimer's Disease In Down Syndrome;
Funder
National Health and Medical Research Council
Funding Amount
$782,418.00
Summary
People with Down syndrome have an extra chromosome 21 and all develop Alzheimer's disease. We are able to delete different parts of chromosome 21 in Down syndrome stem cells and turn these cells into the two main cell types of the brain. By comparing the occurrence of Alzheimer disease with gene expression changes in these gene-edited cell types we can identify the gene-regulatory pathways that cause Alzheimer's disease in Down syndrome and identify novel therapeutic targets for sporadic Alzheim ....People with Down syndrome have an extra chromosome 21 and all develop Alzheimer's disease. We are able to delete different parts of chromosome 21 in Down syndrome stem cells and turn these cells into the two main cell types of the brain. By comparing the occurrence of Alzheimer disease with gene expression changes in these gene-edited cell types we can identify the gene-regulatory pathways that cause Alzheimer's disease in Down syndrome and identify novel therapeutic targets for sporadic Alzheimer's disease.Read moreRead less