Improving Oocyte Mitochondrial DNA Copy Number To Enhance Female Reproductive Capacity.
Funder
National Health and Medical Research Council
Funding Amount
$670,867.00
Summary
Eggs with too few copies of mitochondrial DNA either fail to fertilise or arrest during early development. By supplementing eggs with mitochondrial DNA, we have been able to enhance embryo quality and gene expression profiles. By breeding the offspring derived from eggs given mitochondrial supplementation, we will determine if they and their progeny meet normal developmental milestones, regulate the transmission of mitochondrial DNA appropriately, and are healthy and fertile.
Development Of Therapeutically Useful Human Artificial Chromosomes For Gene Delivery And Optimal Gene Expression
Funder
National Health and Medical Research Council
Funding Amount
$496,986.00
Summary
Gene therapy is an exciting new form of treatment for genetic disorders aimed at providing long-term correction of the problems at source - namely the affected gene. The biggest technical hurdle facing gene therapy is to be able to deliver the therapeutic genes efficiently and safely into patient cells. Many gene therapy protocols are currently being trialled clinically. These protocols, based mostly on the use of attenuated viruses to deliver the genes, carry potential risks to the patients in ....Gene therapy is an exciting new form of treatment for genetic disorders aimed at providing long-term correction of the problems at source - namely the affected gene. The biggest technical hurdle facing gene therapy is to be able to deliver the therapeutic genes efficiently and safely into patient cells. Many gene therapy protocols are currently being trialled clinically. These protocols, based mostly on the use of attenuated viruses to deliver the genes, carry potential risks to the patients in terms of infection, immune response, and germline modification. We have developed the first stage of a new technology for gene delivery that does not require the use of viruses. This technology is based on the generation of human artificial chromosomes, which are smaller versions of the naturally occurring chromosomes that carry all the genes inside our cells. Safety in these artificial chromosomes comes from the use of entirely human materials for their engineering. These artificial chromosomes also have other advantages over the viral approaches, including allowing large genes to be carried, and providing a permanent cure in a single treatment. We have already successfully constructed, published, and patented a number of first-generation human artificial chromosomes. The current project aims to complete the next proof-of-concept milestone towards the further development of this technology. Specifically, we propose to demonstrate the ability of the artificial chromosomes to carry genes and provide sustainable expression of these genes in cells and in animal models. Success in this study will allow the technology to proceed rapidly into commercialisation and clinical trial as a new improved tool for gene delivery and gene therapy.Read moreRead less
Roles Of The EMT Transcription Factors In Epigenetic Remodelling And Myeloid Cell Transformation.
Funder
National Health and Medical Research Council
Funding Amount
$809,520.00
Summary
This project is based upon our novel discoveries that identified ZEB2 and SNAI1 as novel genes involved in the development of aggressive forms of blood cancer. During the course of this proposal we will find new drug targets and new drug treatment options using existing drugs that will specifically target cancer initiating cells in order to kill aggressive forms of blood cancers that are currently refractory to treatment.
Identifying The Pathological Mechanism Of PCDH19-Girls Clustering Epilepsy
Funder
National Health and Medical Research Council
Funding Amount
$523,988.00
Summary
Changes in the PCDH19 gene are a relatively common cause of epilepsy. To better understand the basis of this disorder, we have developed unique mouse models that mimic the genetic changes and symptoms of this condition. We will perform careful analysis of brain development in these models to determine the primary cause of this condition. These experiments will create greater understanding of how changes in PCDH19 cause epilepsy in girls and facilitate the development of new treatments.
Inflammatory skin disorders, such as psoriasis and dermatitis, are responsible for a large burden of human disease and affect people across alldemographics. Knockout (KO) of TNF signalling members in mice is known to induce skin inflammation. This project proposes to use these genetic mouse models to investigate how and why disruption of particular TNF superfamily members leads to disease and potentially identify new targets for treatment.
Identifying The Critical Pathways Which Regulate Vertebrate Craniofacial Development
Funder
National Health and Medical Research Council
Funding Amount
$552,131.00
Summary
Understanding the genes which underlie human birth defects is of immense clinical importance. Our laboratory is a world-leader investigating a gene responsible for facial skeleton development, Grhl2. With our wide range of models, we will discover how Grhl2 works to ensure the face and skull develop properly during birth.
Engineering MYCN Models Of High-grade Serous Ovarian Cancer (HGSC)
Funder
National Health and Medical Research Council
Funding Amount
$797,478.00
Summary
The most lethal type of ovarian cancer, high-grade serous cancer (HGSC), can be divided into four subtypes based on gene patterns. One subtype involves a set of genes/proteins that, in their specific combination, result in activation of a pathway known as MYCN. As most HGSC start in the fallopian tube, we are using fallopian tube material to make new MYCN HGSC models to observe development in the earliest stages. We hope to generate new tests and treatments for this subtype of ovarian cancer.
The Role Of GRHL-3, A Mammalian Homologue Of Drosophila Grainyhead, In Neural Tube Development
Funder
National Health and Medical Research Council
Funding Amount
$496,500.00
Summary
Spina bifida and anencephaly are two common human congenital malformations that form part of a wide spectrum of mutations known collectively as neural tube defects (NTDs). Patients with the most severe form of spina bifida have a failure of the vertebral column and skin to close over the spinal cord and therefore suffer from limb paralysis and marked bladder and bowel dysfunction. Infants with anencephaly have an open cranial vault and failure of normal brain development and die within the first ....Spina bifida and anencephaly are two common human congenital malformations that form part of a wide spectrum of mutations known collectively as neural tube defects (NTDs). Patients with the most severe form of spina bifida have a failure of the vertebral column and skin to close over the spinal cord and therefore suffer from limb paralysis and marked bladder and bowel dysfunction. Infants with anencephaly have an open cranial vault and failure of normal brain development and die within the first few hours of life. These abnormalities occur frequently (1-1000 live births) and are a direct result of failure of the neural tube to close during embryogenesis. NTDs are influenced by both environmental and genetic factors. The best characterised environmental factor is the dietary supplement folate, which when administered before conception results in a reduction in the incidence of spina bifida. The genetic complexity is evidenced by the array of mouse genetic mutations that give rise to NTDs. One of these mouse mutations, known as Curly tail (ct), has served as the major animal model of human NTDs. This is because the ct mice are resistant to folate administration (like most of the cases of spina bifida currently seen in patients) and because the mice seem to have normal development in virtually all other organ systems. Ironically, the genetic mutation that causes the curly tail phenotype has remained undiscovered for over 50 years. We have now identified the gene mutated in the curly tail mice. This gene is highly conserved in humans suggesting that it will play a similar role in neural tube development in man. The gene, known as GRHL-3, is a descendant of a fly gene critical for development of the nervous system in that organism. The studies we propose here will examine the developmental pathways involved in normal neural tube closure in mice and humans and will impact on our understanding of these devastating congenital malformations.Read moreRead less
Role Of MACROD2 Loss In DNA Repair, Chromosomal Instability And Development Of Colorectal Cancer: Clinical And Therapeutic Implications
Funder
National Health and Medical Research Council
Funding Amount
$772,871.00
Summary
The MACROD2 gene is deleted in one-third of human bowel cancers. We have discovered that MACROD2 deletion causes defective DNA repair and tumour chromosomal instability. Here, we will use novel laboratory models to show that MACROD2 loss actively promotes bowel cancer development. We will test the clinical implication of MACROD2 loss for predicting tumour therapy response and will investigate the potential of exploiting this deficiency for drug targeting.
Exploiting And Defining The Immune Regulatory Activities Of BET Bromodomain Inhibitors
Funder
National Health and Medical Research Council
Funding Amount
$923,222.00
Summary
Immune-based agents such as “checkpoint inhibitors” have the ability to re-awaken our own immune systems and activate previously dormant anti-tumor responses. We have discovered that small molecule inhibitors of gene regulatory proteins called bromodomain proteins act synergistically with checkpoint inhibitors in mouse cancer models. We will define the molecular and biological events underpinning this novel combination approach and assess the effects of the combination across different tumors.