Post-transcriptional Regulation Of Plasminogen Activator Inhibitor 2 Gene Expression
Funder
National Health and Medical Research Council
Funding Amount
$508,838.00
Summary
Plasminogen activator inhibitor type 2 (PAI-2) is a protease inhibitor that has intracellular and extracellular functions. The PAI-2 gene is highly regulated at the level of PAI-2 mRNA stability. We have identified regions within the PAI-2 transcript essential for this regulation and a number of novel proteins that engage these regions. This project is aimed at understanding how these and other proteins control PAI-2 expression at the mRNA level.
Alternative Splicing- A Regulatory Mechanism Determining Self-renewal And Pluripotency Of ES And IPS Cells
Funder
National Health and Medical Research Council
Funding Amount
$664,650.00
Summary
Stem cells hold great promise in cell replacement therapies and may provide models to study human diseases and to screen new pharmaceuticals. For successful future therapeutic applications, a deeper understanding of the molecular mechanisms governing the behavior of stem cells is crucial. In this proposal we will investigate the role of alternative splicing in the control of the fundamental properties of stem cells, and identify target RNAs and gene expression networks regulated by splicing fact ....Stem cells hold great promise in cell replacement therapies and may provide models to study human diseases and to screen new pharmaceuticals. For successful future therapeutic applications, a deeper understanding of the molecular mechanisms governing the behavior of stem cells is crucial. In this proposal we will investigate the role of alternative splicing in the control of the fundamental properties of stem cells, and identify target RNAs and gene expression networks regulated by splicing factors.Read moreRead less
RNA Binding Protein Musashi: Role In Folliculogenesis And Oocyte Development
Funder
National Health and Medical Research Council
Funding Amount
$419,223.00
Summary
Women in Australian have opted for social and economic reasons to delay both marriage and childbirth. Both infertility and congenital abnormality is associated with advancing maternal age as the ovarian pool of oocytes declines in number and quality. In this project we aim to gain an understanding of the molecular mechanisms underpinning healthy oocyte development. Insights gained have the potential to alleviate miscarriage, infertility and congenital abnormalities in Australian families.
The Role Of The Mammalian Grainyhead-like Gene Family In Neural Tube Closure
Funder
National Health and Medical Research Council
Funding Amount
$569,541.00
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. Anencephaly is not compatible with life and affected babies die at birth. In contrast children with spina bifida survive, but suffer from limb paralysis, bowel and bladder dysfunction, learning diff ....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. Anencephaly is not compatible with life and affected babies die at birth. In contrast children with spina bifida survive, but suffer from limb paralysis, bowel and bladder dysfunction, learning difficulties and psycho-social disturbances. Our laboratories have identified a family of genes essential for the colsure of the neural tube in mammals. The aim of this proposal is to understand the mechanisms of action with a view to developing new therapeutics that mey be used preventatively in these conditions. We also hope that these studies may facilitate the development of a genetic test to screen couples at risk.Read moreRead less
Biological, Functional And Radiographic Evaluation Of Autologous Chondrocyte Implantation
Funder
National Health and Medical Research Council
Funding Amount
$307,400.00
Summary
We will test the hypothesis that autologous chondrocyte implantation (ACI) and extensor realignment produces superior clinical, biological and radiographic results when compared with conventional treatment of realignment and debridement. We will specifically address the following aims: 1. Quantify the clinical outcome of ACI compared to the traditionally used treatment of debridement through the use of functional evaluation in a blinded randomised controlled clinical trial; 2. Evaluate the radio ....We will test the hypothesis that autologous chondrocyte implantation (ACI) and extensor realignment produces superior clinical, biological and radiographic results when compared with conventional treatment of realignment and debridement. We will specifically address the following aims: 1. Quantify the clinical outcome of ACI compared to the traditionally used treatment of debridement through the use of functional evaluation in a blinded randomised controlled clinical trial; 2. Evaluate the radiographic changes in the patellofemoral joint that occur as a result of ACI, using high resolution magnetic resonance imaging (MRI) to quantify the regeneration of hyaline articular cartilage; 3. Using the new technique of confocal arthroscopy, we will compare the histologic appearances of the ACI graft and its interface with adjacent articular cartilage; 4. Evaluate patient, surgical and explant chondrocyte characteristics in relation to functional, radiographic and biological outcomes. With respect to the matrix-induced autologous chondrocyte implantation (MACI) technique, we wish to clarify the clinical practice as a definitive treatment for articular cartilage defects. This will be the first randomised, controlled clinical trial of the MACI technique compared to that used by other groups. A positive clinical outcome from this trial will help promote the three cornerstones of this procedure – successful cell culture, efficient surgical procedures, and complimentary postoperative rehabilitation. Furthermore, this research will: a) Enhance the expansion of the MACI technique; b) Encourage development of endoscopic techniques of implantation using a combination of – • Preoperative defect registration with MRI • pre-cut custom patches, implanted with • Computer-assisted navigation techniques: c) Increase the potential to cater for a larger number of patients requiring articular cartilage repair; d) Confirm the long-term durability of regenerated cartilage in the 4th year and beyond; e) Add further commercial value by demonstrating MACI may prevent the onset of osteoarthritis.Read moreRead less
Identification And Characterisation Of Genes Required For Cardiac Morphogenesis
Funder
National Health and Medical Research Council
Funding Amount
$434,706.00
Summary
The heart is the first organ to become functional as an embryo forms, reflecting its critical role in sustaining life. Mistakes that occur as the heart develops have devastating consequences for an individualÍs survival and health. We have identified two zebrafish mutants with heart defects and, using sophisticated imaging and genetic studies, will investigate these defects and identify the genes responsible. This research will improve our understanding of correct and diseased heart formation.
Alternative Splicing Of GLI1 And Its Role In Tumourigenesis
Funder
National Health and Medical Research Council
Funding Amount
$392,640.00
Summary
Gene expression involves the transfer of information from DNA to proteins and is mediated by a third molecule called messenger RNA (mRNA). The process is tightly controlled since unregulated gene expression is harmful and can result in diseases such as developmental disorders and cancer. The genetic information in DNA is first copied to an RNA molecule in a process called transcription. This RNA molecule then undergoes a series of maturation steps before the information it carries can be transla ....Gene expression involves the transfer of information from DNA to proteins and is mediated by a third molecule called messenger RNA (mRNA). The process is tightly controlled since unregulated gene expression is harmful and can result in diseases such as developmental disorders and cancer. The genetic information in DNA is first copied to an RNA molecule in a process called transcription. This RNA molecule then undergoes a series of maturation steps before the information it carries can be translated into a protein. One of these maturation steps involves the removal of sequences (called introns) that do not contain protein coding information from the sequences (called exons) that will be present in the mature mRNA. Some genes contain no introns while others contain 20 or more, which are dispersed throughout the gene. The removal of intron sequences from immature RNA molecules is called splicing and is carried out by a macromolecular complex that recognises the intron sequences, cuts them out of the RNA and then rejoins the RNA to make a contiguous sequence. This process has to be precise otherwise spurious sequences will be present in the mRNA, which will result in the production of abnormal proteins. In addition, for some genes mRNAs are produced that have differences in a portion of their sequence. These alternative sequences are generated by the inclusion or exclusion of alternative exons. Because, RNA splicing is critical to the production of mature mRNAs and because it can generate sequence diversity it is tightly regulated. We have recently found that expression of a cancer gene (called GLI1) is regulated in part by the use of alternative GLI1 mRNAs. Moreover, we found that the expression of one of these alternative GLI1 mRNAs is associated with skin cancer. In this project we will investigate the molecular mechanisms that regulate alternative splicing in GLI1 and identify whether changes in these mechanisms result in cancer.Read moreRead less
Post-transcriptional Gene Regulation In RNA-granules
Funder
National Health and Medical Research Council
Funding Amount
$533,274.00
Summary
This project is focused on understanding pathways that regulate RNA metabolism and development. Using the powerful C. elegans model organism (nonpathogenic roundworm) we will undertake experiments to identify pathways that regulate how some mRNAs are stored and later activated during reproduction. The outcomes of these experiments should provide many interesting clues as to how development is regulated by posttranscriptional mechanisms, and have broad relevance to other tissues and organisms.