Diabetes mellitus is a disease reaching epidemic proprotions in the western world. Nearly one million Australians have diabetes mellitus; many of these people will suffer debilitating secondary complications, resulting in significant morbidity and mortality at considerable social and economic cost. Complications include heart attack, stroke, kidney disaease, blindness and limb amputation. There are two forms of diabetes (type I and type 2), and though there are considerable differences in their ....Diabetes mellitus is a disease reaching epidemic proprotions in the western world. Nearly one million Australians have diabetes mellitus; many of these people will suffer debilitating secondary complications, resulting in significant morbidity and mortality at considerable social and economic cost. Complications include heart attack, stroke, kidney disaease, blindness and limb amputation. There are two forms of diabetes (type I and type 2), and though there are considerable differences in their etiology, both forms result in an inability of the body to control blood sugar levels. Beta cells release the hormone insulin, which regulates blood sugar levels. Current knowledge suggests that a loss of beta cell mass is important for both diseases. For type I diabetes the beta cells are destroyed by the immune system. Though for type 2 diabetes the causes are less clear, it is apparent that the beta cells are dying. Our research is focused on understanding the molecular pathways that control beta cell survival and regulate their death. Such knowledge would help us understand the complex processes leading to the development of diabetes. Furthermore, we could use this knowledge in the design of genetic engineering strategies to create 'death-defying' beta cells, as a potential therapeutic strategy for the treatment of diabetes.Read moreRead less
Investigation Of Pancreatic Insulin-secreting Cell Function And Survival
Funder
National Health and Medical Research Council
Funding Amount
$375,750.00
Summary
Diabetes remains a major health problem in Australia. Both type 1 and type 2 diabetes is eventually due to pancreatic insulin-producing beta-cell destruction, which is caused mainly by the cell death, so called 'apoptosis' or programmed suicide of the cells. Thus, attempting to protect beta-cells against death and rescue their insulin secretory function is emerging as a strategy for the treatment of diabetes. However, how the beta-cells undergo death and how to protect the cell death are still n ....Diabetes remains a major health problem in Australia. Both type 1 and type 2 diabetes is eventually due to pancreatic insulin-producing beta-cell destruction, which is caused mainly by the cell death, so called 'apoptosis' or programmed suicide of the cells. Thus, attempting to protect beta-cells against death and rescue their insulin secretory function is emerging as a strategy for the treatment of diabetes. However, how the beta-cells undergo death and how to protect the cell death are still not completely understood. We have recently discovered a new protein, named sphingosine kinase, that is a strong protector against cell death. We also found that this enzyme is involved in process of insulin secretion. Thus, this application seeks to establish a dual role of this enzyme in protecting beta-cells from death and promoting insulin secretion by the cells. This will ultimately allow us to create new therapeutic strategy to target this protein for the management of diabetes.Read moreRead less
Enhancing Peripheral Clearance Of Beta Amyloid As A Treatment For Alzheimers Disease
Funder
National Health and Medical Research Council
Funding Amount
$548,681.00
Summary
Amyloid-beta (abeta) accumulation in the brain is a key step in the development of Alzheimer's disease, with potential therapies focusing on its clearance. Compounds that bind abeta in blood have been shown to alter brain abeta levels. We will assess the efficacy of a novel abeta-binding peptide to promote peripheral clearance of brain-derived abeta in a mouse model of AD. Such a drug would be effective in sporadic AD, where the efflux transport, clearance and degradation systems are defective.
Truncating Presenilin Mutations And Their Effects On Gamma-secretase Activity, Tau And Beta-catenin
Funder
National Health and Medical Research Council
Funding Amount
$414,005.00
Summary
Alzheimer's disease (AD) and cancer are increasingly important both in terms of human suffering and the burden of care it imposes on society and the economy. Sporadic (non-inherited) AD is the most common form of dementia but is poorly understood. The PRESENILIN genes, PSEN1 and PSEN2, are the major sites for mutations causing inherited AD and are also implicated in cancer. Using the zebrafish embryo model we have discovered that, contrary to current thought, mutations that truncate presenilin p ....Alzheimer's disease (AD) and cancer are increasingly important both in terms of human suffering and the burden of care it imposes on society and the economy. Sporadic (non-inherited) AD is the most common form of dementia but is poorly understood. The PRESENILIN genes, PSEN1 and PSEN2, are the major sites for mutations causing inherited AD and are also implicated in cancer. Using the zebrafish embryo model we have discovered that, contrary to current thought, mutations that truncate presenilin proteins potently suppress normal presenilin activity. (They are so called, dominant negatives). This means that they are lethal for embryo development and explains why such mutations have never been found in inherited AD. Notably, this discovery could only be made using a subtle form of gene manipulation that is possible in zebrafish embryos. Our work has also established the first assay for the non-apoptotic (non-cell death) function of PSEN2 and has shown that PSEN2 activity is inhibited by truncated PSEN1. This is the first indication of possible interaction between PSEN1 and PSEN2 proteins at normal physiological expression levels. Loss of presenilin activity promotes cancer. Truncated presenilin proteins could be produced by errors in gene transcription (aberrant transcript splicing) common in cancerous cells. This suggests that truncated, dominant negative forms of presenilin produced through aberrant splicing (or mutation in precancerous cells) might be common in tumour formation. The proposed research will define the region of PSEN1 in which truncation leads to dominant negative activity. This will allow further examination of the role of presenilins in the cell signalling pathways involved in AD and cancer. We will also investigate the role that age-related truncation of presenilins in human cells can play in the formation of sporadic AD. This may reveal a common molecular link between the inherited and sporadic forms of this disease.Read moreRead less
The Role Of Growth Differentiation Factor 9 (GDF9) In Human Fertility
Funder
National Health and Medical Research Council
Funding Amount
$568,811.00
Summary
IVF comes at a substantial financial burden to the Australia health system through Medicare. There is mounting evidence to suggest that egg quality is the key limiting factor in female fertility. The aim of this proposal is to produce a key egg-secreted protein which is critical for the ability of the egg to be fertilized and to develop a diagnostic assay to measure egg quality to improve the treatment of infertility.
Expansion, Differentiation And Functional Analysis Of In Vitro Derived Pdx1+ Pancreatic Progenitors
Funder
National Health and Medical Research Council
Funding Amount
$540,075.00
Summary
Type 1 diabetes is a condition that arises when the body's immune system destroys insulin-producing beta cells within the pancreas. Recent studies have shown that normal glucose control can be restored by replacing the missing beta cells by transplantation of cells from deceased donors. However, the demand for transplant material outweighs supply. The work described in this application seeks to define how insulin-producing beta cells can be derived in the laboratory from embryonic stem cells .