Antisense Oligonucleotide Induced Exon Skipping As A Treatment For Duchenne Muscular Dystrophy
Funder
National Health and Medical Research Council
Funding Amount
$363,055.00
Summary
Duchenne muscular dystrophy (DMD) is the most common severe muscle wasting disease that affects boys. A defect in the dystrophin gene (typically a frameshift or nonsense mutation) precludes the synthesis of any functional protein. Becker muscular dystrophy (BMD) is a milder condition that also arises from defects in the dystrophin gene but in these cases, the mutations are usually in-frame deletions that allow some functional protein to be synthesised. There have been significant limitations to ....Duchenne muscular dystrophy (DMD) is the most common severe muscle wasting disease that affects boys. A defect in the dystrophin gene (typically a frameshift or nonsense mutation) precludes the synthesis of any functional protein. Becker muscular dystrophy (BMD) is a milder condition that also arises from defects in the dystrophin gene but in these cases, the mutations are usually in-frame deletions that allow some functional protein to be synthesised. There have been significant limitations to dystrophin gene replacement therapies, due to the nature of the target (muscle fibres) and the size and complexity of the gene. This project will investigate an alternative genetic approach in cells expressing dystrophin (this gene is transcribed and processed differently in a variety cell types), whereby antisense oligonucleotides are used to redirect the processing of dystrophin pre-mRNA in the region of the DMD mutation. Although the DMD mutation would still be present at the gene level, the disease-causing mutation would be removed during the processing of the dystrophin pre-mRNA. Once a nonsense mutation has been removed or the reading frame restored from a DMD transcript, the resultant engineered dystrophin mRNA could be translated into a functional Becker-like protein.Read moreRead less
Cell-specific Regulation Of The MicroRNA/RNAi Pathway
Funder
National Health and Medical Research Council
Funding Amount
$659,390.00
Summary
MicroRNAs are a group of molecules that are critical for controlling the activity of genes. They function in a diverse range of biological systems, such the brain and immune system. Although we know that these molecules are important, how they are made in cells is still poorly understood. Because these molecules have potential therapeutic applications, it is essential that we gain a precise understanding of their biology before we will be able to apply these to medicine.
MRNA Surveillance In Human Genetic Disease: Molecular Determinants Of Nonsense-mediated MRNA Decay
Funder
National Health and Medical Research Council
Funding Amount
$371,275.00
Summary
In about 1/3 of inherited disorders the mutations introduce an abnormal stop signal into the gene so that cells risk producing truncated or erroneous proteins. To prevent this cells have developed control surveillance mechanisms called Nonsense Mediated mRNA Decay (NMD). We have found a new form of NMD and our studies are directed determining how this works in cells, which genes use this pathway, and the consequences of this for human genetic disease.
MicroRNAs are a group of molecules that are critical for controlling the activity of genes. They function in a diverse range of biological systems, from early embryonic development to adult organs, such as the brain and immune system. Although we know that these molecules are important, there remain major gaps in our understanding of how they are produced. Thus, the goal of our research is to understand how cells make these molecules.
An unusual type of molecule, circular RNA, was recently discovered to be present in human cells, and to potentially affect the ability of cancer cells in invade and metastasise. We will investigate the interactions these circular RNA molecules have with other molecules, what functions they have, and how they affect cancer cell invasion and metastasis. This could potentially reveal new ways of intervening in cancer metastasis, leading to new therapeutic modalities for cancer patients.
Investigation Of 5-methylcytosine And MicroRNA Function In Eukaryotic RNA
Funder
National Health and Medical Research Council
Funding Amount
$311,991.00
Summary
It is hypothesised that 5-methylcytosine in RNA represents a novel regulatory code affecting transcriptome utilisation in ways currently hidden from view. To unravel this code and its (patho)- physiological role(s), this study proposes to generate and interpret comprehensive transcriptome-scale maps of 5-methylcytosine in a range of cellular contexts chosen to reveal links to cellular differentiation, growth, and malignant transformation.
A New Function For Histone Variants In The Tissue-specific Regulation Of Pre-mRNA Splicing
Funder
National Health and Medical Research Council
Funding Amount
$657,224.00
Summary
It is estimated that greater than 90% of human genes undergo alternative RNA splicing, which can explain how protein diversity is achieved with a limited number of genes. However, how alternative splicing patterns are established remains poorly understood but is an important question given that 15-50% of human disease mutations are associated with changes to the splicing patterns of RNA. We have uncovered a new splicing mechanism, which involves changing the way DNA is packaged in a cell.
Treatment Of Virally-induced Cancers By RNA Interference.
Funder
National Health and Medical Research Council
Funding Amount
$389,250.00
Summary
Cancers require certain mutations and the over expression of genes to cause disease. Each cancer has a unique set of gene changes thus making it difficult to treat. However, it has become clear that the normal control mechanisms of many cancers are still intact but are repressed by the over expression of these oncogenes (or cancer genes). By turning off these oncogenes we can restore normal control to the cell and the cancer will die normally. We will use a new method of gene targeting called RN ....Cancers require certain mutations and the over expression of genes to cause disease. Each cancer has a unique set of gene changes thus making it difficult to treat. However, it has become clear that the normal control mechanisms of many cancers are still intact but are repressed by the over expression of these oncogenes (or cancer genes). By turning off these oncogenes we can restore normal control to the cell and the cancer will die normally. We will use a new method of gene targeting called RNA interference to turn off oncogenes. RNA interference involves treatment of cells with a small peice of genetic material that provides the cell with an identity pattern of the gene to be eliminated. The cell takes the pattern and turms off the genes expression. As long as the pattern only turns off the cancer gene all other genes will remain normal. We will test this using cervical cancer as a model as all these cancers are caused by infection with a virus that carries 2 oncogenes. It is these virus oncogenes that cause the cancer and therefore we know the exact target genes that need to be turned off. Most importantly these genes are not present in normal cells making it safe to target them by RNA interference. We have gathered an expert group of investigators with experience in cervical cancer and cancer genetics to address this problem. If successful we will have proven this new technique can work against cervical cancer and this method could then be applied to any cancer. We would then be able to start human trials. Cervical cancer kills over 300 women in Australia each year, is the leading cause of cancer death in Aboriginal women, is 2nd most common cancer of women in the world and is the leading cancer killer worldwide in women under 50.Read moreRead less
DBHS Protein RNA Interactions In Health And Disease
Funder
National Health and Medical Research Council
Funding Amount
$748,073.00
Summary
In cells involved in cancer, the interactions of DBHS proteins with each other, and with nucleic acids (eg RNA) are different to those in healthy cells. Only once we understand how DBHS proteins interact with some important RNA molecules, and how these interactions affect cell biology, can we begin to open up new pathways for therapy. This proposal aims at understanding and explaining this complex aspect of biology.
Molecular Insights Into Long Noncoding RNA-protein Complexes: Important Gene Regulators In Cancer
Funder
National Health and Medical Research Council
Funding Amount
$388,927.00
Summary
Cancer cells turn good genes off and bad ones on: but how do they do this? Recent breakthroughs suggest that noncoding RNA, produced from so-called ‘junk’ DNA, is important. One such noncoding RNA forms paraspeckles, a novel component of the cell machinery. Here, we will pick apart the way paraspeckles are organised and function, to develop them as a prototype for designing anti-cancer treatments against noncoding RNAs.