Novel Strategies To Promote Myelin Repair In The Brain
Funder
National Health and Medical Research Council
Funding Amount
$597,865.00
Summary
Demyelinating diseases of the central nervous system such as multiple sclerosis have a lifelong impact and devastating impact on quality of life. We have identified that a growth factor, brain derived neurotrophic factor (BDNF), plays an important role in promoting myelination during development. We will investigate the potential of translating these findings into effective clinical treatment, by characterising the efficacy of BDNF in promoting CNS remyelination after a demyelinating insult.
Directed Molecular Evolution Of G Protein-coupled Receptors For Stable And Functional Expression In Escherichia Coli
Funder
National Health and Medical Research Council
Funding Amount
$383,479.00
Summary
Approximately half of all prescription drugs on the market act on G protein coupled receptors (GPCRs). The mechanisms underlying GPCR function are mainly unknown due to a lack of structural information. No solved structures exist for any of the estimated 800 human GPCRs, making it difficult to design new drugs. By applying advanced protein engineering techniques I aim to produce human GPCRs in bacteria to ultimately acquire structural information, which will enable novel drug development.
Molecular neurobiology of the GABAB receptor: Studies of heteromeric receptor function and signalling. The G protein-coupled receptor (GPCR) for the inhibitory transmitter gamma- aminobutyric acid (GABA) is a unique heterodimer. Molecular analyses will be undertaken to provide insights into its signalling mechanisms and functional regulation. Investigations employing point mutant and chimeric receptors will analyse how ligand binding to the extracellular domain of the GABA-BR1 subunit triggers ....Molecular neurobiology of the GABAB receptor: Studies of heteromeric receptor function and signalling. The G protein-coupled receptor (GPCR) for the inhibitory transmitter gamma- aminobutyric acid (GABA) is a unique heterodimer. Molecular analyses will be undertaken to provide insights into its signalling mechanisms and functional regulation. Investigations employing point mutant and chimeric receptors will analyse how ligand binding to the extracellular domain of the GABA-BR1 subunit triggers G protein-coupling to the intracellular portion of the GABA-BR2 subunit. Focus will be on different modes of GPCR signalling, including constitutive activity and roles for membrane and cytosolic regulatory proteins. Targeted studies of GABAB receptor subunits will provide new information on the mechanistic regulation of GPCR signalling.Read moreRead less
Assembly And Function Of Two Interacting Oncogenic Scaffolds
Funder
National Health and Medical Research Council
Funding Amount
$705,585.00
Summary
Aberrant signaling by the protein kinase superfamily is a known driving force for many cancers and inflammatory diseases. Recently, a subset of kinase-like proteins, termed pseudokinases, have emerged as crucial regulators of kinase signalling pathways. This proposal focuses on elucidating the scaffolding function and assembly of two pseudokinases, termed SgK223 and SgK269, which display oncogenic properties and aims to understand how their signalling abilities are subverted in a disease state.
Design And Engineering Of Adnectins For Diagnosis And Therapy
Funder
National Health and Medical Research Council
Funding Amount
$803,152.00
Summary
This project aims to engineer a naturally-occurring human protein, called an adnectin, to produce molecules that are able to bind specific targets in the human body, and as such may be used in the diagnosis and therapy of a range of diseases.
Alzheimer’s disease (AD), is the most common form of dementia, accounting for between 50-70% of all cases. There is general agreement that current treatments for AD/dementia are inadequate so new treatment strategies are desperately needed. I am addressing these challenges by developing new technologies to generate next generation treatments for AD.
Crosstalk Between The Repressive Histone Methyltransferases PRC2 And G9A: Structure-function Investigation To Open New Therapeutic Opportunities
Funder
National Health and Medical Research Council
Funding Amount
$595,205.00
Summary
The gene expression programs need to be precisely regulated and the misregulation of these programs can cause a broad range of human diseases. My research will focus on two protein complexes, which heavily contribute to the regulation of gene expression. My study will open a new path for developing new therapeutic strategies.
A redox sensor and triple receptor function for guanylyl cyclase. Nitric oxide (NO) protects from blood vessel spasms and clot formation. Conversely, insufficient NO occurs in cardiovascular disease. Life-saving drugs like glycerol trinitrate supply more NO to blood vessels, however these drugs are limited in their action when their target protein (NOGC) is decreased or defective, eg. in hypertension or arteriosclerosis. We have elucidated the reason for this defect and simultaneously discovered ....A redox sensor and triple receptor function for guanylyl cyclase. Nitric oxide (NO) protects from blood vessel spasms and clot formation. Conversely, insufficient NO occurs in cardiovascular disease. Life-saving drugs like glycerol trinitrate supply more NO to blood vessels, however these drugs are limited in their action when their target protein (NOGC) is decreased or defective, eg. in hypertension or arteriosclerosis. We have elucidated the reason for this defect and simultaneously discovered an entirely novel group of drugs which activate NOGC without NO. Impressively, these drugs are most effective in diseased blood vessels. The aim is the development of novel blood pressure lowering/anti-anginal drugs with higher effectiveness and less side-effects because they work in an entirely new way.Read moreRead less
The Role Of Copper In Ubiquitin-dependent Protein Degradation In Alzheimer's Disease
Funder
National Health and Medical Research Council
Funding Amount
$588,622.00
Summary
Ubiquitin’s are small proteins that tag other proteins in a process known as “Ubiquitination”. Often this is to target them for degradation once they are no longer needed i.e. to take out the rubbish. This process is disrupted in Alzheimer’s disease (AD), which may contribute to the disease. This project aims to find out if copper, an essential metal for life, is required for this process. Drugs that are designed to deliver copper to brain cells have been effective in small AD clinical trials.
Spatial And Temporal Dimensions Of Mu-opioid Receptor Signalling: Implications For The Development Of Tolerance
Funder
National Health and Medical Research Council
Funding Amount
$799,316.00
Summary
The use of morphine as an analgesic is still limited by undesirable side effects such as tolerance. Despite decades of research, the mechanisms behind the development of tolerance are poorly understood. The ? opioid receptor is a protein expressed at the surface of the cells that is the target of morphine. This project will investigate the signalling events triggered by opioids with unprecedented resolution and will aim to elucidate why morphine elicits more tolerance than other opioid drugs.