Liver Cell Transplantation For The Treatment Of Liver Based Metabolic Diseases.
Funder
National Health and Medical Research Council
Funding Amount
$444,143.00
Summary
We propose to investigate the role of liver cell transplantation (LCT) for the therapy of inherited liver-based metabolic diseases using a methylmalonic aciduria (MMA) mouse model. LCT provides an exciting alternative to whole organ transplantation. Initially it was considered liver cells would be immunopriviledged. This has not proven to be the case. Immune modulation will be important. We will also examine immune modulation using antibodies to optimise longterm survival of allogeneic cells.
Molecular Basis Of Transgenerational Epigenetic Inheritance In Mammals
Funder
National Health and Medical Research Council
Funding Amount
$477,965.00
Summary
While it has long been recognised that it is not just DNA, but chromosomes, that are passed from the gametes to the embryo, the non-DNA component was thought to carry no information with respect to the offspring's ultimate phenotype. However, there is now evidence that the non-DNA component, the epigenetic component, can play a role in the inheritance of phenotype in mammals. This study will attempt to determine the molecular nature of this phenomenon.
A Saturation Screen For Modifiers Of Epigenetic Reprogramming In The Mouse: Phase II
Funder
National Health and Medical Research Council
Funding Amount
$1,374,820.00
Summary
The building of a complex organism, such as a human embryo, is a self-directed process driven by the genetic information inherited from the parents. As the cells differentiate into a diverse array of tissues, the genetic information does not change. What does change is the epigenetic state of the genome in each cell type. We still understand little about this epigenetic reprogramming except that mistakes in the process lead to death and disease. Our work aims to address this lack of knowledge
Genetic And Molecular Basis Of Congenital Cataracts
Funder
National Health and Medical Research Council
Funding Amount
$454,510.00
Summary
Cataracts are caused when the lens of the eye (which focuses light), loses transparency. They typically occur in older individuals, but can also occur in children, even as early as from birth. They usually result in severe vision impairment which can result in complete blindness. The only treatment is invasive surgery where the outcomes are poor, particulary in very young children. This research aims to discover the genes that cause cataract in children and to investigate how cataracts form. We ....Cataracts are caused when the lens of the eye (which focuses light), loses transparency. They typically occur in older individuals, but can also occur in children, even as early as from birth. They usually result in severe vision impairment which can result in complete blindness. The only treatment is invasive surgery where the outcomes are poor, particulary in very young children. This research aims to discover the genes that cause cataract in children and to investigate how cataracts form. We are working with several large Australian families that have severe childhood cataracts in order to identify the specific genes that cause their disease. This is achieved through an investigation of the entire genome of these families which allows us to precisely pinpoint any genetic changes. We can then look for these changes in the genes in other childhood cataract patients as well as in adults with cataracts. This information will increase our understanding of how the lens of the eye works and how cataracts can form. One gene that can cause cataracts has already been identified, this is the Nance-Horan Syndrome gene. We will investigate the role of this gene in the lens of the eye. This gene also causes other severe disabilities including mental retardation. The exact function of this gene is unknown but by determining how it works we will be able to better understand cataract formation and mental retardation, with the ultimate aim of developing better diagnosis and timely treatment for these disorders.Read moreRead less
Mutation Analysis Of Novel Candidate Genes For X-linked Charcot Marie Tooth (CMTX3) Neuropathy.
Funder
National Health and Medical Research Council
Funding Amount
$191,434.00
Summary
Our goal is to explore how peripheral nerves degenerate by identifying the gene mutation causing an X linked form of Charcot Marie Tooth neuropathy (CMTX3). Using bioinformatic resources and state of the art gene mutation scanning we will complete characterisation and systematic screening of candidate genes and novel transcripts in the region. Discovery of this gene will provide a means to determine mechanisms causing axonal degeneration and lead to targeted therapeutic treatment strategies.
Infectious Large Capacity Vectors For Gene Therapy
Funder
National Health and Medical Research Council
Funding Amount
$374,625.00
Summary
The next 25 to 50 years will witness the culmination of a demographic shift in the age of the population which will be associated with an increasing importance of both inherited predispositions to late-onset chronic, complex diseases and natural degenerative processes. Medicine has historically sought to manage and cure the symptoms of disease. The focus for therapy has begun to switch from alleviating the ailments to establishing and resolving their causes. On the back of the Human Genome Proje ....The next 25 to 50 years will witness the culmination of a demographic shift in the age of the population which will be associated with an increasing importance of both inherited predispositions to late-onset chronic, complex diseases and natural degenerative processes. Medicine has historically sought to manage and cure the symptoms of disease. The focus for therapy has begun to switch from alleviating the ailments to establishing and resolving their causes. On the back of the Human Genome Project, genetics research will identify genes that are central to these processes, leading to gene-based medicine. Some of this new treatment will be drug-based but an alternative is the correction of the defective genes themselves gene therapy to either replace inherited faulty genes or to provide novel or modified genes that may help the repair and maintenance of tissue, or combat abnormal processes such as cancer. Gene therapy is a field still in its infancy with just a few qualified successes reported in the past few years. Persistent expression of a transgene at therapeutic levels is required for successful gene therapy. Most of the currently used vector and virus systems have a small capacity and usually employ a reduced (cDNA) copy of the transgene lacking natural control mechanisms. These are prone to vector loss and promiscuous expression or loss of expression. The delivery of genomic DNA up to 20 times this size would enable genes to be transferred in entirety, including their natural regulatory elements. This project aims to develop a vector system based on Herpesviruses that tackles some of the problems with the current generation of gene therapy vectors. This system is particularly aimed at providing long-term gene expresssion at physiological levels and safe, efficient delivery systems through the use of genomic DNA.Read moreRead less
Inside our cells is a complex traffic system. The vehicles are vesicles that come in different shapes and sizes and travel to specific destinations in the cell to deliver cargo such as: surface growth factor receptors that are to have their signalling terminated, proteins and lipids destined for the cell wall for growth or development (like neurite outgrowth) and proteins and hormones destined for secretion (like neurotransmitter release). More than 100 human genetic disorders map to defects in ....Inside our cells is a complex traffic system. The vehicles are vesicles that come in different shapes and sizes and travel to specific destinations in the cell to deliver cargo such as: surface growth factor receptors that are to have their signalling terminated, proteins and lipids destined for the cell wall for growth or development (like neurite outgrowth) and proteins and hormones destined for secretion (like neurotransmitter release). More than 100 human genetic disorders map to defects in one of the components of this system. Proteins called small GTPases provide order for this traffic and allow specific cargo to reach specific destinations. They regulate cell functions by acting as switches, turning biochemical processes on and off inside the cell. Ral is a small GTPase enzyme found in brain and broadly distributed in other cells. We have discovered that Ral is part of a large signalling complex. When activated Ral stimulates effectors, either the exocyst or RalBP1. In turn, mild oxidative stress controls a Ral inhibitor protein called ERp57. The research proposed aims to establish the functional role for the Ral signalling complex in cells. We will determine with which vesicle trafficking events Ral is associated, which effector it utilises in that pathway, and how that effector directs the traffic. We will also map the steps that may lead to inactivation of Ral via ERp57 in cells, and propose that this is mediated by mild oxidative stress. Techniques of molecular biology, biochemistry, molecular biology, proteomics and microscopy will be used to establish these functions. The research will lead to increased knowledge of the significance of this protein to cellular and particularly neuronal cell function. This forms the basis for understanding normal cell function and for identification of further factors causing diseases of vesicle transport. In time, such research aids in the development of specific therapies for sufferers of such diseases.Read moreRead less
MRNA Surveillance In Human Disease: Molecular Determinants Of Nonsense-mediated MRNA Decay
Funder
National Health and Medical Research Council
Funding Amount
$474,517.00
Summary
Inherited diseases are a common cause of human disability, illness and suffering. It has been estimated that 5-10% of the population will be affected by disorders with a genetic component. Thus studies on mechanisms of inherited diseases, especially those relating to genetic mechanisms with relevance across a wide range of individual disorders and gene mutations, are of great significance in diagnosis, molecular pathology and the eventual development of therapeutics. While there are many types o ....Inherited diseases are a common cause of human disability, illness and suffering. It has been estimated that 5-10% of the population will be affected by disorders with a genetic component. Thus studies on mechanisms of inherited diseases, especially those relating to genetic mechanisms with relevance across a wide range of individual disorders and gene mutations, are of great significance in diagnosis, molecular pathology and the eventual development of therapeutics. While there are many types of mutations, one relatively common type is called a premature termination mutation. Premature termination mutations introduce an inappropriate genetic signal that tells the cells to stop the formation of proteins before they are complete. This would result in the production of a protein that is shorter than normal, and these short proteins could be quite abnormal and drastically affect the normal function of cells. To overcome this, cells have developed elegant strategies that involve the deployment of quality control, or surveillance, mechanisms to remove the mutant gene product before it can be converted into an abnormal protein. This process is called nonsense mediated decay. Nonsense mediated decay is a complex process and some of the key components have been identified by studies on a small number of genes. However, our studies have identified several previously unknown aspects of the process that suggest that the currently held view of how nonsense mediated decay works is only the beginning of the story and further important complexity exists. The proposed research will explore the basic mechanisms of the surveillance process and determine the signals that initiate nonsense mediated decay. Since premature termination mutations cause one-third of all inherited genetic disorders, our studies will provide new insights into the surveillance mechanisms and will have wide applicability to our understanding of the basis of inherited disease.Read moreRead less
Regulation Of Hedgehog Signalling Through Intracellular Trafficking Events
Funder
National Health and Medical Research Council
Funding Amount
$220,500.00
Summary
The hedgehog signalling cascade plays a role in forming almost every organ of the body during development of an embryo. Perturbation of the function of key members of this pathway during embryonic development often results in death in utero or severe childhood abnormalities. In addition, disruption to this pathway also results in a range of cancers, most notably the extremely common skin cancer basal cell carcinoma. In this proposal we aim to investigate in detail the regulatory mechanisms which ....The hedgehog signalling cascade plays a role in forming almost every organ of the body during development of an embryo. Perturbation of the function of key members of this pathway during embryonic development often results in death in utero or severe childhood abnormalities. In addition, disruption to this pathway also results in a range of cancers, most notably the extremely common skin cancer basal cell carcinoma. In this proposal we aim to investigate in detail the regulatory mechanisms which operate to ensure that this complex pathway of interacting molecules functions correctly during embryonic development. By understanding how this regulation occurs we will gain valuable insight into how disruption of this pathway results in such a range of disease, as well as into how agents which modulate this pathway may potentially act in a therapeutic setting.Read moreRead less
The Role Of The Liver In The Pathogenesis Of Hereditary Haemochromatosis
Funder
National Health and Medical Research Council
Funding Amount
$592,023.00
Summary
Hereditary Haemochromatosis (HH) type 1 is a very common inherited disorder of iron metabolism that affects 1:200 Australians. HH is usually caused by mutations in the HFE gene and leads to excessive absorption of dietary iron and progressive iron loading of organs, particularly the liver. Undetected, progressive iron accumulation may have serious clinical consequences including cirrhosis, arthritis, diabetes mellitus and heart disease. The role of HFE in normal iron metabolism and how mutations ....Hereditary Haemochromatosis (HH) type 1 is a very common inherited disorder of iron metabolism that affects 1:200 Australians. HH is usually caused by mutations in the HFE gene and leads to excessive absorption of dietary iron and progressive iron loading of organs, particularly the liver. Undetected, progressive iron accumulation may have serious clinical consequences including cirrhosis, arthritis, diabetes mellitus and heart disease. The role of HFE in normal iron metabolism and how mutations in HFE lead to the development of Fe overload are unknown. Other types of HH have been identified that have similar clinical characteristics to HH type 1 which are due to mutations in hepcidin or haemojuvelin (type 2) and transferrin receptor 2 genes (type 3). It is thought that HFE acts together with these molecules in the same or closely related pathways to regulate iron metabolism. It is hypothesised that HFE and transferrin receptor 2 act as sensors of body iron levels which signal to the iron stores regulator, hepcidin to control the absorption of dietary iron and the deposition of iron in the liver. In this study, we will use mice with mutations in HFE and transferrin receptor 2 which have many of the characteristics of human HH type 1 and type 3 to identify 1) how HFE and transferrin receptor 2 sense body iron levels, 2) how they signal to hepcidin to regulate iron metabolism and 3) how mutations in HFE and transferrin receptor 2 lead to dysfunctional sensing of iron levels and impaired signalling to hepcidin causing increased iron absorption and liver iron overload in HH. This study will provide new knowledge about the role of HFE and other closely related molecules in the regulation of normal iron metabolism and the development of iron overload in HH and identify the potential of molecules such as hepcidin for therapeutical use for the prevention and treatment of iron overload.Read moreRead less