Wounds, burns and scalds are frequent injuries which can lead to deformity, disfigurement and loss of movement. We have shown that the cytoskeletal protein, Flightless I (FliI), is an important regulator of wound repair. We plan to further investigate FliI in wound and burn injuries using new cell-specific transgenic animal models and to develop a new FliI-antibody based therapy to treat wound and burn injuries.
Inherited Muscle Disorders - Gene Discovery, Pathobiology And Therapy.
Funder
National Health and Medical Research Council
Funding Amount
$1,750,277.00
Summary
The project proposed by Professors Nigel Laing and Kathryn North and Dr Kristen Nowak is based upon the results of their successful identification of disease genes for genetic muscle diseases. The project is divided into three parts. In the first part of the project, the research team will identify further novel disease genes, some of which they are already close to finding. In the second part of the project the team will determine how the mutations they have identified in the disease genes actu ....The project proposed by Professors Nigel Laing and Kathryn North and Dr Kristen Nowak is based upon the results of their successful identification of disease genes for genetic muscle diseases. The project is divided into three parts. In the first part of the project, the research team will identify further novel disease genes, some of which they are already close to finding. In the second part of the project the team will determine how the mutations they have identified in the disease genes actually cause the diseases. The aim of this work is to discover targets that may ultimately lead to new therapies for these muscle diseases. In the third and final part of the project, the team will pursue one possible therapeutic approach, which is based upon the understanding of the diseases the researchers have gained from their previous studies. There are currently no cures for these muscle diseases, though symptoms can be treated. The team will determine whether heart actin can replace muscle actin in skeletal muscle and thus might treat the muscle disease.Read moreRead less
In type 1 diabetes the body becomes deficient in insulin production from pancreatic b cells because the immune system mistakenly attacks and destroys b cells as if they were an invading infection. Recurrence of autoimmune destruction of b cells also occurs following transplantation of whole pancreas or islet cells and may occur in the future when other engineered insulin producing cells are transplanted. The focus of this program is to better understand how b cells are killed by the immune syste ....In type 1 diabetes the body becomes deficient in insulin production from pancreatic b cells because the immune system mistakenly attacks and destroys b cells as if they were an invading infection. Recurrence of autoimmune destruction of b cells also occurs following transplantation of whole pancreas or islet cells and may occur in the future when other engineered insulin producing cells are transplanted. The focus of this program is to better understand how b cells are killed by the immune system and to test ways of protecting beta cells from these mechanisms. Because of the inaccessibility of the pancreas to study (particularly biopsy) in humans with diabetes, much of the proposed work will be carried out in b cells derived from non-obese diabetic (NOD) mice, the best available mouse model of type 1 diabetes. It is clear from the literature that a molecule called perforin found in cytoxic T lymphocytes (CTL) is a major, if not the major, mechanism the immune system uses against b cells. For this reason we will try to better understand the interaction between b cells and perforin and ultimately design ways of them from perforin-mediated cell death. It is equally clear that there are other mechanisms besides perforin that can cause b cell death and the program will also address discovery of these mechanisms and new ways to block them. Beta cells in NOD mice will be protected from perforin or other mechanisms by the addition of protective genes or removal of harmful genes using transgenic knockout technology. Addition or removal of genes involved in cell death can be done systematically and each protocol tested using NOD mouse model. The process of cell death that b cell undergo in type 1 diabetes is called apoptosis. Apoptosis is a general mechanism by which cells of all types die. Experts in the biology of apoptosis and perforin are important members of the program, providing the opportunity to translate the latest advances in cell death research to diabetes. This research addresses several of the specific research areas of interest to JDRF. It focuses on the prevention of b cell death in individuals with type 1 diabetes receiving islet transplants. It may be applicable in the future to protection of stem or precursor cells that have been differentiated into b cells or even to devising strategies to prevent the development of diabetes.Read moreRead less
Vitamin D Synthesis Within Osteoblasts Increases Bone Mineral By Regulating Remodelling: Is This The Link Between Vitamin D Status And Fractures?
Funder
National Health and Medical Research Council
Funding Amount
$627,082.00
Summary
This project will contribute to understanding mechanism of vitamin D action within bone to modulate bone resorption and offers the exciting prospect of identifying the mechanism by which an adequate vitamin D status can reduce the risk of osteoporotic hip fractures. Thus, this project has great potential to improve community health by being able to recommend vitamin D supplementation made on the basis of maintaining normal bone cell function with psarticular reference to modulating bone resorpti ....This project will contribute to understanding mechanism of vitamin D action within bone to modulate bone resorption and offers the exciting prospect of identifying the mechanism by which an adequate vitamin D status can reduce the risk of osteoporotic hip fractures. Thus, this project has great potential to improve community health by being able to recommend vitamin D supplementation made on the basis of maintaining normal bone cell function with psarticular reference to modulating bone resorption.Read moreRead less
Mechanisms Of Insulin Resistance And Diabetes Susceptibility
Funder
National Health and Medical Research Council
Funding Amount
$633,783.00
Summary
The two main forms of diabetes - types 1 (T1D) and 2 (T2D) - pose a major problem. It is difficult to identify what causes diabetes. Recently, people at risk of T1D were found to have insulin resistance, a condition thought typical only of T2D. Excitingly, we discovered that the best T1D animal model also shows insulin resistance, and we used it to map important genes. We will now identify these genes. This will help us understand the disease process and to develop better treatments for it.
Building a death-defying islet beta cell Type I diabetes results when the cells that produce insulin (the islet beta cells) are killed by the immune system. The beta cell, like any other cell in the body, can be induced to die by activation of a process that leads to cell suicide. During this process, enzymes dismantle the structure of the cell and the remains are eaten by neighboring cells. In diabetes, the stimulus for beta cell suicide is provided by a number of agents most of which are made ....Building a death-defying islet beta cell Type I diabetes results when the cells that produce insulin (the islet beta cells) are killed by the immune system. The beta cell, like any other cell in the body, can be induced to die by activation of a process that leads to cell suicide. During this process, enzymes dismantle the structure of the cell and the remains are eaten by neighboring cells. In diabetes, the stimulus for beta cell suicide is provided by a number of agents most of which are made by the T cells of the immune system. Our aim is to interfere with this cell suicide process and engineer a beta cell that can resist T cell attack. Because genetically manipulated mice provide the flexibility we need to add and subtract genes from the beta cell we will use them as a model to build a death-defying beta cell. We will investigate three strategies. Firstly, cells will be engineered to express a molecule (CD30 ligand) which recognizes a protein on the surface of the attacking T cells and in so doing, sends a signal to the T cells to stop proliferating. Secondly, we will remove proteins (CD95, TNFRI) from the surface of the beta cell, that attacking T cells use to set in motion the cell suicide process. Thirdly, we will engineer beta cells that express inside themselves, cell death inhibitor proteins (Bcl-2, CrmA, p35) that can prevent the automatic process of cell suicide. It is our hope that studies with death-defying beta cells will find a new way to manipulate islet tissue for transplantation. In patients with diabetes, the beta cells have all been destroyed but the attacking T cells still remain. As a result, transplants of new beta cells are rapidly damaged. Beta cells that can resist ongoing immune attack may survive well enough to reverse the symptoms of diabetes. The success of this research could have an impact on a cure for diabetes.Read moreRead less
Biological Role And Partners Of The LIM Domain Protein LMO4 In Breast Epithelium
Funder
National Health and Medical Research Council
Funding Amount
$120,181.00
Summary
Breast cancer is the most common cancer affecting women, with 1 in 14 developing this disease. Although treatment of breast cancer has substantially improved over the last few years, 30% of women diagnosed with this cancer will die from it. One major focus of cancer research is the identification of genes involved in tumour development and definition of their precise role in cancer cells. The design of effective therapeutic inhibitors of cancer requires an understanding of the basic molecular an ....Breast cancer is the most common cancer affecting women, with 1 in 14 developing this disease. Although treatment of breast cancer has substantially improved over the last few years, 30% of women diagnosed with this cancer will die from it. One major focus of cancer research is the identification of genes involved in tumour development and definition of their precise role in cancer cells. The design of effective therapeutic inhibitors of cancer requires an understanding of the basic molecular and cellular biology behind the genetic changes thought to contribute to cancer. The focus of our research is to understand normal cellular mechanisms that drive growth and differentiation of breast tissue, and those changes that lead to breast cancer. Nuclear regulatory proteins have been implicated in many different types of cancers and leukaemias. We aim to identify the key regulators in breast tissue, characterising both their structural properties and biological roles, with the ultimate view of understanding how they divert a normal cell to a cancerous cell.Read moreRead less
Defining The Cellular Basis For Therapeutic Angiogenesis: Characterisation Of Endothelial Progenitor Cell Populations
Funder
National Health and Medical Research Council
Funding Amount
$100,943.00
Summary
Cardiovascular disease is the leading cause of death in the Australia. Endothelial progenitor cells (EPCs), similar to stem cells, have strong self-renewal capabilities and the ability to mature further. There has been immense interest in using EPCs as they are believed to have a role in the growth and repair of blood vessels. This research systematically studies two candidate EPCs, the early EPC and the outgrowth EPC (OEC), and potentially paves the way for using EPCs to treat heart disease.
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