Funded Applications:
Cell Death Pathways and Type 1 Diabetes new
CIA: Professor. Joseph Trapani
Administering Institution: University of Melbourne
Budget: $2,998,000 over 5 years
Project Summary:
Loss of insulin-producing beta cells leads to type 1 diabetes and rejection of allogeneic islet transplants. The aim of this program is to discover ways of protecting beta cells from damage. We will do this by investigating whether blocking crucial regulators of cell death can protect mouse and human beta cells from destruction in vitro and in vivo. In doing so, we aim to prevent diabetes in mice and potentially improve the survival of islet grafts after transplantation.
Which transgenic pig will be used for islet transplantation in humans? new
CIA: Professor Anthony d’Apice
Administering Institution: St. Vincent’s Health,
Budget: $3,000,000 over 5 years
Project Summary:
We propose that xenotransplantation of pig islets will cure Type 1 diabetes. This program will generate genetically modified pigs to overcome the molecular differences between pigs and humans by removing a pig gene and inserting several human genes. In addition, we will add immunosuppressive genes and so minimise the need for drug treatment of the diabetic recipient. We will test our hypothesis by transplanting islets from these genetically modified pigs into baboons. We suggest that this will provide an inexhaustible supply of islets for transplantation.
Beta cell mass and function in Type I diabetes and islet transplantation new
CIA: Dr Shane Grey
Administering Institution: GARVAN INSTITUTE OF MEDICAL RESEARCH
Budget: $3,037,750 over 5 years
Project Summary:
This research program will examine the cellular and molecular mechanisms underlying the loss of Beta cell mass and function:
- During the pathogenesis of Type 1 Diabetes Mellitus (T1D); and
- Following islet transplantation.
Though these processes have traditionally been considered to be purely immune-mediated, it is now clear that the response of the beta cell is critical to the final outcome of the auto-immune process and response to therapeutic interventions. Thus the complex interactions between the cellular and soluble constituents of the immune system, plus the effects of a deregulated metabolic milieu, are integrated at the beta cell. This in turn activates a series of complex transcriptional programs in the beta cell that together determine the beta cells ultimate functional status and survival.
We will use knowledge gained from studying these processes to drive the development of novel therapeutic targets and strategies to improve the success of immune-based and transplantation-based therapies.
Derivation of Pancreatic B-cells from Embryonic Stem Cells new
CIA: Professor Ed Stanley
Administering Institution: Monash University
Budget: $2,941,880 over 5 years n
Project Summary:
People with type 1 diabetes require regular insulin injections because the organ that normally makes insulin, the pancreas, no longer functions. The goal of this program is to derive human fetal pancreas tissues from embryonic stem cells. Such tissue could be used to replace the missing insulin producing cells in people with type 1 diabetes. The program brings together expertise in ES cell biology at Monash University and the leading diabetes research at the Walter and Eliza Hall Institute.
Role of heparan sulfate, heparanase and heparanase inhibitors in the development and prevention of Type I Diabetes new
CIA: Professor Christopher Parish
Administering Institution: The Australian National University
Budget: $3,000,000 over 5 years
Project Summary:
Our recent studies have shown that a special protein (an enzyme called heparanase) and the special carbohydrate (heparan sulfate or HS) that it degrades, play a previously unrecognised role in the development of Type I diabetes (T1D) in mice. We will explore whether destructive immune cells use heparanase to damage insulin-producing islets and deplete them of HS, resulting in islet cell death and T1D. We will develop new agents to inhibit this damage, prevent T1D and protect islet transplants.
Gene Based Treatment Strategies for Diabetic Retinopathy
CIA: Professor Elizabeth Rakoczy
Administering Institution: University of Western Australia
Budget: $2.63 million
Project Summary:
Diabetic retinopathy is the leading cause of blindness in the working population of developed countries and it is destruction of the light-detecting part of the retina. In addition, this treatment is 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.
The project combines several very recent scientific advances into one strategy to combat diabetic retinopathy at a molecular level. Vision is arguably 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. This project seeks to develop such an animal model. In addition, the project aims to identify new therapeutic agents from molecules that are naturally produced by the retina while fighting the disease. Finally, these agents will be tested and evaluated in the animal models. The most successful therapeutic candidates will then be further developed for human trials.
If successful, this approach could have a major impact on the treatment of diabetic retinopathy and possibly on all diabetic vascular diseases.
Hypoglycaemia in Young Patients with Type 1 Diabetes: Pathophysiology, Predisposition and Prevention Strategies
CIA: Dr Timothy Jones
Administering Institution: University of Western Australia
Budget: $2.68 million
Project Summary:
Low blood sugar (hypoglycemia) can occur in people with Type 1 diabetes even if they closely monitor their glucose levels and inject insulin consistently. The condition can cause confusion, abnormal behaviour, seizures - and in extreme cases, coma and death. The fear of hypoglycemia is unrelenting for patients and their families, significantly impairing quality of life but also severely restricting attempts to control diabetes.
Dr Jones will lead a team of 12 researchers in a study of hypoglycemia to address important unanswered questions. They will examine in detail how the protective mechanisms against hypoglycemia are damaged in diabetes. They also will study more closely those situations that are known to predispose people with diabetes to hypoglycemia, such as sleep and exercise, as well as how the brain is affected as blood sugar levels fall. They hope to devise management strategies that will lessen the effect of hypoglycemia.
The project will bring together an active team of experienced researchers who will address this medical problem. It will build on an established population database of children and adolescents with diabetes in Western Australia as well as completing a DNA bank of these patients and their families.
A Preclinical Model of Pig Islet Xenotransplanation as a Treatment of Type 1 Diabetes
CIA: Associate Professor Phillip O'Connell
Administering Institution: University of Sydney, Westmead Hospital, Sydney
Budget: $4.37 million
Project Summary:
Although a great number of people with diabetes could benefit from islet transplantation, the procedure is severely limited by the shortage of available islets from donors. One possible solution to this problem is to use islets from pigs that have been genetically modified so that their cells are less foreign to the human immune system. Researchers think the right genetic alteration could prevent the severe rejection that usually occurs with transplants between species.
A research team of 11 scientists, led by Dr O'Connell, will concentrate on four main challenges that must be addressed if this cross-species transplant, or 'xenotransplant', is to succeed: (1) Determine the best source of insulin-secreting tissue to use-whether it is newborn or fetal pig islet cell clusters, or islets from adult pigs; (2) Overcome strong rejection response to pig tissue; (3) Identify the right combination of drugs to give to suppress rejection; (4) Produce new types of genetically modified pigs that will provide islets tissue that will work in humans.
The long-term goal of the project is to make islet cell transplantation a safe and effective option for all patients with diabetes.
Molecular Analysis of Pathways in Diabetes Studies
CIA: Professor Christopher Goodnow
Administering Institution: John Curtin School of Medical Research, Canberra
Budget: $3.3 million
Project Summary:
Diabetes has been linked to a large number of genes, most of them still unknown. The genes and proteins work together in molecular pathways that either promote the development of diabetes or protect against it.
The researchers will induce genetic mutations in mice and then breed them to see how the loss of a specific gene affects function and metabolism in the offspring. The offspring will be analysed for inherited defects that cause beta cell loss or failure, as well as mutations that actually protect animals from beta cell damage or immune attack. The researchers will sequence the DNA and identify diabetes-regulating genes and biochemical pathways in animals that appear especially susceptible or resistant to the development of diabetes.
Finding diabetes-regulating genes and pathways in the mice will illuminate corresponding genes in humans.
Novel Strategies for the Early Detection, Prevention and Treatment of the Microvascular Complications of Diabetes
CIA: Associate Professor Richard Gilbert
Administering Institution: St. Vincent's Hospital, Melbourne
Budget: $4.72 million
Project Summary:
The deterioration of blood vessels plays a central role in the development of eye and kidney complications that occur with diabetes, robbing victims of sight and life. Despite important medical advances in treating diabetes, about one-third of those with the disease develop kidney complications, and a similar proportion develop visual loss from diabetic retinopathy. Associate Professor Richard Gilbert will head a 14-member team exploring the mechanisms that lead to the development and progression of these complications seeking to develop strategies for their treatment and prevention.
The scientific group includes established diabetes researchers and investigators from other areas of academic medicine, such as cardiovascular biology and applied genetics. In addition to collaborating with each other, the researchers will work with bio-technology and pharmaceutical drug discovery programs to develop new treatment strategies for diabetic kidney and eye disease.
T-Cell Mechanisms of B-Cell Destruction
CIA: Dr Thomas Kay
Administering Institution: St. Vincent's Institute of Medical Research
Budget: $3.1 million
Project Summary:
Diabetes occurs when a person's own immune cells destroy insulin-producing beta cells in the pancreas. A research team led by Dr Kay will study a subset of immune cells, called T-cells, that target the beta cells and cause them to die in a process called apoptosis. The researchers will work to elucidate the molecular pathways of T-cell mediated apoptosis and test ways of protecting beta cells from these mechanisms. The T-cells interact with beta cells through specific protein molecules that act as signals to trigger this apoptosis.
Because the pancreas is inaccessible for study in humans, the scientists will conduct much of the proposed work in specially bred mice that exhibit diabetes-like conditions. The researchers will try protecting the beta cells by adding protecting genes or removing harmful genes from the animals. They hope to identify ways to prevent beta cell apoptosis, which could prevent or slow the onset of diabetes.
Creating Beta Cells to Cure Type 1 Diabetes
CIA: Dr Andrew Elefanty
Administering Institution: Monash University
Budget: $4.26 million
Project Summary:
In Type 1 diabetes, the cells that normally produce insulin (beta cells) are damaged and cannot provide the insulin needed by the body. Dr Elefanty's team will try to create new beta cells, by studying the molecules that are responsible for producing beta cells during development. The researchers will work in cell culture systems to learn how to coax cells to develop into insulin-producing beta cells, and whether these methods can be used to restore function to the patients own, damaged beta cells. These experiments have the potential to provide a completely new therapeutic approach to diabetes.