The Organisation Of The Chromosome Into Distinct Epigenetic Domains And Its Link With Development And Disease
Funder
National Health and Medical Research Council
Funding Amount
$521,591.00
Summary
This investigation will show that a key cellular mechanism that determines how the chromosome is organised into stable domains is by changing the make-up of chromosomal domains through the replacement of histone proteins with specialised forms of histones called variants . This fundamental research will provide important new information on how chromosomes become unstable in cancer.
Regulation Of The Histone Code By Histone Variants
Funder
National Health and Medical Research Council
Funding Amount
$589,425.00
Summary
A fundamental unanswered question in biology is how a single fertilized mammalian cell can differentiate into a multicellular organism when every differentiated cell type inherits the same DNA. Fundamental to this development process is that different sets of genes are expressed in different cell types. This investigation will show that a key mechanism to regulate gene expression is the way our DNA is covered with specifically modified and altered forms of histone proteins.
Engineered Histones As DNA Carriers With Application In Therapeutic Gene Delivery
Funder
National Health and Medical Research Council
Funding Amount
$417,750.00
Summary
We intend to apply our knowledge of protein transport to the nucleus to enhance the delivery of DNA to target cells. This relates to the use of gene therapy to treat genetic defects such as inborn errors of metabolism, where a disease-causing lack-of-function mutation can be overcome by engineering cells within the organism which express, in the necessary quantities and in response to the appropriate regulatory signals, the particular component which is lacking. A limiting factor in gene therapy ....We intend to apply our knowledge of protein transport to the nucleus to enhance the delivery of DNA to target cells. This relates to the use of gene therapy to treat genetic defects such as inborn errors of metabolism, where a disease-causing lack-of-function mutation can be overcome by engineering cells within the organism which express, in the necessary quantities and in response to the appropriate regulatory signals, the particular component which is lacking. A limiting factor in gene therapy approaches is the low efficiency of nuclear uptake of introduced DNA, where it has been estimated that < 1% of the DNA taken up is actually expressed. Our proposal seeks to develop approaches to enhance non-viral-mediated gene delivery, in particular by optimising this critical, limiting step of the delivery of exogenous DNA to the nucleus. We intend to apply knowledge from studies of nuclear targeting and chromatin assembly to improve gene transfer technologies. We will build on our work showing that specific signals for nuclear import - nuclear targeting signals (NTSs) - can be used to enhance nuclear gene delivery and expression. Since DNA in the normal cellular context is in the form of chromatin - a specific complex with proteins such as histones - we intend to use reconstituted chromatin as the transfecting DNA, whereby histones engineered to include NTSs and other modular sequence elements will be used. Chromatin should not only enable NTSs and other sequence modules to be linked to the DNA but also protect against nuclease-mediated degradation prior to nuclear entry, condense the DNA to enable more efficient cellular-nuclear entry, and ensure expression of the transfected reporter gene by presenting it to the cell in a physiological context. Our approaches should contribute to bringing gene therapy closer to reality in the clinic.Read moreRead less
The Distinctive Roles Of Tissue Transglutaminase Isoforms In Neuroblastoma
Funder
National Health and Medical Research Council
Funding Amount
$311,567.00
Summary
Neuroblastoma is the commonest solid tumour in early childhood. Neuroblastoma caused by N-Myc oncogene accounts for about one third of the disease and represents a more aggressive subtype with a worse clinical outcome. This project aims to identify factors responsible for N-Myc-induced neuroblastoma initiation and factors sensitizing neuroblastoma cells to anti-cancer drugs, and to provide the basis for clinical trials of a combination therapy in children with neuroblastoma.
Functional Evaluation Of BRCA1 & BRCA2 Unclassified Sequence Variants And Identification Of Critical Pathogenic Domains.
Funder
National Health and Medical Research Council
Funding Amount
$331,312.00
Summary
The major genes that predispose to hereditary breast cancer are called BRCA1 and BRCA2. Most mutations in these genes cause the protein product to be truncated and inactive. However there are many families in which such truncating mutations are not found, but instead there are sequence changes that slightly alter the protein product. It is often difficult to predict whether these sequence variants are likely to cause hereditary breast cancer simply by looking at the position and nature of the se ....The major genes that predispose to hereditary breast cancer are called BRCA1 and BRCA2. Most mutations in these genes cause the protein product to be truncated and inactive. However there are many families in which such truncating mutations are not found, but instead there are sequence changes that slightly alter the protein product. It is often difficult to predict whether these sequence variants are likely to cause hereditary breast cancer simply by looking at the position and nature of the sequence change. Consequently, it is not possible to offer informative genetic counselling to these women or their at-risk family members. Assessment of the potential pathogenicity and functional significance of these unclassified sequence variants will be directly useful with regard to the clinical management of these women and their families, and will develop our current understanding of how different domains of these genes contribute to their role as cancer susceptibility genes.Read moreRead less
The human hepatitis B virus (HBV) is a member of the hepadnavirus family that includes a number of other very similar host-specific viruses. Acute HBV infection can produce extreme variation in disease, ranging from asymptomatic infection, to acute transient hepatitis with jaundice, or fulminant hepatitis leading to liver failure (Hollinger, 1996). The identification of viral genes that affect the severity of disease is a major current goal in medical virology. For example, there is considerable ....The human hepatitis B virus (HBV) is a member of the hepadnavirus family that includes a number of other very similar host-specific viruses. Acute HBV infection can produce extreme variation in disease, ranging from asymptomatic infection, to acute transient hepatitis with jaundice, or fulminant hepatitis leading to liver failure (Hollinger, 1996). The identification of viral genes that affect the severity of disease is a major current goal in medical virology. For example, there is considerable interest in identifying the genes of the influenza genome responsible for high mortality outbreaks; with the human immunodeficiency virus, the virus that causes AIDS, variants deleted in the nef gene region cause a less rapidly progressing infection and have attracted attention as a possible prototype for an attenuated vaccine. We propose to investigate how the different genes of hepadnaviruses affect the course of infection and type of disease produced. Studies will be performed in ducks infected with the duck hepatitis B virus (DHBV) as these animals provide the only model system available in Australia. We will study both experimentally and naturally derived DHBV variants to explore the effects of genetic changes on the outcome of infection. This will enhance our understanding of this virus family and will provide models for comparison with HBV infection. This knowledge may then contribute to our ability to manage and control HBV disease in humans.Read moreRead less