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
Biochemical Basis Of Islet Beta-cell Compensation And Failure In Normal Pregnancy And Gestational Diabetes Mellitus
Funder
National Health and Medical Research Council
Funding Amount
$480,828.00
Summary
The factors causing the current world-wide crisis of rapidly rising diabetes prevalence remain poorly understood. Of potential major importance, however, is the hypothesis that abnormalities in the maternal metabolic environment, as occur in gestational diabetes (GDM) (diabetes that develops in pregnancy), result in abnormal development of metabolic systems in the baby resulting in higher risk of adult onset diabetes in the babies. Therefore, it is of importance to understand the mechanisms caus ....The factors causing the current world-wide crisis of rapidly rising diabetes prevalence remain poorly understood. Of potential major importance, however, is the hypothesis that abnormalities in the maternal metabolic environment, as occur in gestational diabetes (GDM) (diabetes that develops in pregnancy), result in abnormal development of metabolic systems in the baby resulting in higher risk of adult onset diabetes in the babies. Therefore, it is of importance to understand the mechanisms causing GDM, such that effective measures can be developed to counter this passing on of diabetes risk from mother to baby. It is known that a key factor causing GDM is failure of maternal pancreatic islet beta-cells to compensate for increased demands for insulin production in pregnancy. Poorly understood, however, are the cellular mechanisms of islet beta-cell compensation in normal pregnancy and failure of this compensation in GDM pregnancy. We have recently shown that there is a pathway of fat metabolism (triglyceride- free fatty acid cycle) within the islet beta-cell that has an important role in amplyfing insulin secretion necessary to maintain normal blood glucose and protecting the islets from failure in obese rats. The major focus of this project is to test the hypothesis that this pathway has a key role in the adaptation of pancreatic islets to normal pregnancy and its dysfunction contributes to the causation of GDM. Of great interest from preliminary findings is that a master regulator of glucose and fat metabolism, PGC1alpha, is markedly reduced in islets during normal pregnancy. Studies will also be directed to PGC1alpha's role in islet adaptation to pregnancy and failure in GDM. We expect that successful completion of this project will lead to the development of highly targeted counter measures to prevent GDM and to slow and reverse the current epidemic of diabetes.Read moreRead less
This is a study of the biological system of epigenetics. Every cell in our body has the same genetics, or library of information contained in the form of DNA sequence. Epigenetics is the system that controls how this DNA is used in a particular situation, or what books are opened and read. During embryonic development, cells know what they want to become, e.g., a muscle cell, and, once they take on an identity, remember that they are when they duplicate themselves during growth. Epigenetics does ....This is a study of the biological system of epigenetics. Every cell in our body has the same genetics, or library of information contained in the form of DNA sequence. Epigenetics is the system that controls how this DNA is used in a particular situation, or what books are opened and read. During embryonic development, cells know what they want to become, e.g., a muscle cell, and, once they take on an identity, remember that they are when they duplicate themselves during growth. Epigenetics does not achieve this through changing genetics the library always stays intact. Rather, it acts by using proteins or chemicals to make DNA functional in one way, or another. Genomic imprinting is a special type of epigenetics. While an embryo has received identical genetic information from each of its parents, the epigenetic information received from each parent was not entirely the same. Some genes which behave differently according to what parent they came from. For example, a gene that makes a growth factor protein is active only if received from the father. If received from the mother, it is inactive, and makes no protein. Genes behaving in this way are known as imprinted genes. We are trying to discover what epigenetic mechanisms are behind this behaviour of imprinted genes. One way we are approaching this problem is to study germ cells the cells giving rise to eggs and sperm. These cells are unusual in that their imprinted genes behave in the same way regardless of whether they were received from the mother or father, i.e., like any other gene. If we can understand why this is the case, we will be better able to understand why imprinted genes behave the way they do in the rest of the cells of the body. Broadly, the mechanisms we uncover should further our understanding of germ cell development, gene expression, and disease. Perturbations in the epigenetic profile are likely causes of human disease, including cancer.Read moreRead less
A small number of babies die unexpectedly while still in the womb: the numbers are much higher than those dying from Sudden Infant Death Syndrome (SIDS). Some of these babies slow their movements down in the days before death. It would be very helpful to be able to accurately monitor babies' movements in the womb so that we could help the few babies who need it, and so prevent poor outcomes. Mothers feel their babies moving, but it's often hard for them to pick up all the movements that do occur ....A small number of babies die unexpectedly while still in the womb: the numbers are much higher than those dying from Sudden Infant Death Syndrome (SIDS). Some of these babies slow their movements down in the days before death. It would be very helpful to be able to accurately monitor babies' movements in the womb so that we could help the few babies who need it, and so prevent poor outcomes. Mothers feel their babies moving, but it's often hard for them to pick up all the movements that do occur. The best way of measuring babies' movements is during an ultrasound. However, that's expensive and means that the pregnant mother needs to lie still for about half an hour to have this testing done. We are developing a way of recording babies' movements, which still lets the pregnant woman continue with her normal activities. We will do this using an AMBULATORY FETAL ACTIVITY MONITOR, which is an accelerometer, like an advanced pedometer. The ambulatory fetal activity monitor will measure the activity of the unborn baby during pregnancy, looking at the number of times s-he moves and how simple or complex the movements are. We expect that the unborn baby who is not getting enough nutrition during the pregnancy will have fewer movements than other unborn babies. This project involves checking that movements picked up by the ambulatory fetal activity monitor are the same as movements seen on an ultrasound. We will then monitor a large number of pregnant women with healthy and possibly unhealthy babies, to help identify the babies who need help. Once we have this information, we will be able to use it in the future to possibly prevent poor outcomes in those babies who do need help.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
Analysis Of Factors Governing Globin Gene Expression
Funder
National Health and Medical Research Council
Funding Amount
$512,996.00
Summary
Hemoglobin is the major protein in red blood cells and is essential for the transport of oxygen from the lungs to the tissues. The disorders of hemoglobin production are the commonest genetic diseases world-wide. These diseases can be markedly improved with elevation of the form of hemoglobin produced by the developing embryo, fetal hemoglobin. We have identified key factors important for fetal gene expression. Our goal is to translate these findings into therapies for the hemoglobin disorders.