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
Hormonal Control Of Serotli Cell Maturation And Function
Funder
National Health and Medical Research Council
Funding Amount
$512,898.00
Summary
This project will determine the key roles of androgen in the Sertoli cell, a unique highly specialised cell that provides essential nutritional and structural support for sperm production. Androgen acts via the androgen receptor (AR), which is vital for initiating and maintaining sperm development. In current NHMRC-funded research we successfully established new mouse models designed to study AR, in particular its regulation of gene expression, in the Sertoli cell. We revealed that genomic AR ac ....This project will determine the key roles of androgen in the Sertoli cell, a unique highly specialised cell that provides essential nutritional and structural support for sperm production. Androgen acts via the androgen receptor (AR), which is vital for initiating and maintaining sperm development. In current NHMRC-funded research we successfully established new mouse models designed to study AR, in particular its regulation of gene expression, in the Sertoli cell. We revealed that genomic AR activity within Sertoli cells is essential for 'induction' of complete sperm development. Ongoing work will develop unique 'inducible' transgenic models that will allow, for the first time, selective analysis of Sertoli AR in both 'developing' and 'adult' testes. Our innovative models will allow AR function to be switched on or off at any stage of development, providing unique opportunity to determine the key AR-regulated factors and pathways controlling induction, maintenance or restoration of sperm production. In past NHMRC research we created a novel transgenic model to study another major reproductive hormone, FSH. Using the hormone-deficient background of 'hpg' mice, we found that androgen and FSH act synergistically in the developing 'meiotic' germ cells that form sperm. Using the latest microarray gene technology we generated datasets of androgen-regulated genes with or without FSH activity, which combined with our unique transgenic AR and FSH models, will be used to identify key pathways, including those enhanced by androgen-FSH synergism, in the early testicular response. Our research will provide new knowledge of the precise roles and pathways of testicular AR actions, to ultimately identify key genetic and regulatory factors as targets for significantly improved therapy for male infertility, gonadal tumours, or contraception.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
The Sertoli Cell: Master Regulator Of Hormone-induced Spermatogenic Development
Funder
National Health and Medical Research Council
Funding Amount
$563,536.00
Summary
This project will determine the key roles of major hormones (testosterone, follicle-stimulating hormone, Vitamin A) in Sertoli cells, unique highly specialised cells found in the testis that provide essential nutritional and structural support for sperm production. This research will provide new understanding of the biological pathways controlling sperm development, leading to new molecular targets for infertility or cancer treatment or diagnosis, or new contraceptive strategies for men.
Gene Based Treatment Strategies For Diabetic Retinopathy
Funder
National Health and Medical Research Council
Funding Amount
$2,630,000.00
Summary
Diabetic retinopathy is the leading cause of blindness in the working population of developed countries and it is an increasing problem in the developing world. Present therapy involves extensive laser destruction of the light-detecting part of he retina. In addition, it is not only effective when administered at an appropriate stage in the disease process. Consequently, there is an urgent need for the development of better, prophylactic, easily administrable and cheaper therapies. This project ....Diabetic retinopathy is the leading cause of blindness in the working population of developed countries and it is an increasing problem in the developing world. Present therapy involves extensive laser destruction of the light-detecting part of he retina. In addition, it is not only effective when administered at an appropriate stage in the disease process. Consequently, there is an urgent need for the development of better, prophylactic, easily administrable and cheaper therapies. This project aims to develop a potentially permanent solution to alleviate diabetes-related blindness in the world. The project combines several very recent scientific advances into one strategy to combat diabetic retinopathy at a molecular level. Vision is our most important sensory organ that cannot be replaced. Thus, human trials can only be conducted following extensive animal safety and efficacy trials. To date the development of new therapies has been seriously hampered by the lack of appropriate, easy to reproduce animal models for different stages of diabetic retinopathy. In addition, it aims to identify new therapeutic agents from molecules that are naturally produced by the retina while fighting the disease. Finally, tested and evaluated in the animal models. The most successful therapeutic candidates will then be further developed for human trials.If successful, our approach will potentially have a major impact on the treatment of diabetic retinopathy and possibly on all diabetic vascular diseases. A single injection might only be necessary to prevent the development of diabetic retinopathy, which would represent a significant weapon in the management of patients. In addition, successful application of secretion gene therapy in the eye might open up the possibility to introduce the same concept for the treatment of larger organs undergoing microvascular changes as a result of diabetes.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