IGF BINDING PROTEIN-2 A MODULATOR OF IGF ACTION IN DEVELOPING AND NEOPLASTIC NEURONAL CELLS.
Funder
National Health and Medical Research Council
Funding Amount
$436,980.00
Summary
In early life the brain undergoes rapid growth and remodelling, a process regulated by many factors including the insulin-like growth factor (IGF) system, which potently enhances nerve cell (neuron) survival. Similarly, this system is active in response to brain injury such a stroke, but it may also enhance tumor survival. The regulation of availability of IGFs to the neuron is critical in all these processes. IGF binding protein-2 (IGFBP-2), which is highly abundant in the developing or damaged ....In early life the brain undergoes rapid growth and remodelling, a process regulated by many factors including the insulin-like growth factor (IGF) system, which potently enhances nerve cell (neuron) survival. Similarly, this system is active in response to brain injury such a stroke, but it may also enhance tumor survival. The regulation of availability of IGFs to the neuron is critical in all these processes. IGF binding protein-2 (IGFBP-2), which is highly abundant in the developing or damaged brain, and in tumours, plays a key role on the surface of neurons in regulating IGF availability. We have shown that IGFBP-2 associates with a specialised protein on the nerve cells, where it is further processed to smaller fragments. We believe that these processes are reactivated following brain injury or in cancer states where IGFBP-2 is highly abundant. We propose to determine how IGFBP-2 influences IGF action on the nerve cell surface, and to further ascertain the function of each step in this process. We will achieve this by examining the effects of the mutated version of IGFBP-2, designed to either prevent its binding to the cell surface or its processing to smaller fragments. We will use various human and mouse nerve cell for these studies, which will not only provide greater understanding of the regulation of IGF availability to developing brain cell, but also point to how these processes may be involved in enhancement of recovery from injury or stroke, or possibly in acceleration of tumour growth. The finding of this study will offer the potential for new and exciting treatment designed to alter the function of the IGF system, to either make it more active in response to brain injury or stroke, or less active in brain tumours.Read moreRead less
Novel Regulators Of Glucose Metabolism And Inflammation In Adipose Tissue Of Females
Funder
National Health and Medical Research Council
Funding Amount
$282,830.00
Summary
Obesity is a common problem which can lead to development of diabetes and heart disease. One of the major mechanisms by which obesity leads to these diseases involves a defect in the ability of insulin to stimulate uptake of glucose into cells. We have found that excess of the sex hormone testosterone in women can contribute to this defect in tissues. This study will investigate why testosterone causes this defect in females and whether this defect can be prevented using existing drug therapies.
Hypoglycaemia In Young Patients With Type 1 Diabetes: Pathophysiology, Predisposition And Preventive Strategies
Funder
National Health and Medical Research Council
Funding Amount
$2,680,000.00
Summary
The vision of this proposal is to bring together an active team of experienced investigators that will address important clinical problems affecting the management of children and adolescents with type 1 diabetes. Along with facilities and resources already under development, the program will further establish a core of investigators dedicated to patient centred and clinical research that will facilitate scientific advances to be put into practice. The incidence of type 1 diabetes is continuing ....The vision of this proposal is to bring together an active team of experienced investigators that will address important clinical problems affecting the management of children and adolescents with type 1 diabetes. Along with facilities and resources already under development, the program will further establish a core of investigators dedicated to patient centred and clinical research that will facilitate scientific advances to be put into practice. The incidence of type 1 diabetes is continuing to increase particularly in the young. As we enter the 21st century, insulin treatment aimed at restoring blood glucose levels as close to the normal as possible remains the most effective way to prevent the devastating long-term complications of the disease. Unfortunately this is difficult to achieve largely because insulin therapy is frequently associated with the development of low blood glucose or hypoglycaemia. Hyperglycaemia results in unpleasant symptoms if mild but if severe it can produce convulsions or unconsciousness. The fear of hypoglycaemia is ever present for the patient and their family, this not only significantly impairs quality of life but importantly also severely restricts attempts to control diabetes. One of the major goals of this research program will be to address important unanswered questions related to the development of hyperglycaemia in children and adolescents with diabetes. The research team will examine in detail the protective physiological mechanisms against hyperglycaemia that are deranged in diabetes, they will also study more closely those situations that are known to predispose to hyperglycaemia such as sleep and exercise as well as how the brain is affected as blood glucose falls. By taking this approach we hope to be able to devise management strategies that will lessen the impact of hyperglycaemia in diabetes treatment. It is anticipated that this in turn will contribute to the prevention of diabetes complications as well as reduce the burden of the disease for the patient and his or her family. A second goal of this research program will be to develop an internationally unique resource that will be available to all diabetes investigators. We will build on an already established population based database of all the children and adolescents with diabetes in Western Australia as well as complete a DNA bank of these patients and their families. Thus in addition to bringing together an effective team of researchers, this program will further develop resources that can be central to addressing other important questions related to the causes of diabetes and its complications.Read moreRead less
The Role Of Liver Fructose-1,6-phosphatase (FBPase) In Body Weight Regulation
Funder
National Health and Medical Research Council
Funding Amount
$494,718.00
Summary
We have shown that fructose-1,6-bisphosphatase (FBPase), an enzyme important in producing sugar from the liver and one that is connected to Type 2 diabetes, does not cause an increase in sugar production when there is more of the enzyme in mouse livers. It does, however, lower both body weight and the amount of food the mice consume. We therefore hypothesise that liver FBPase is important in controlling body weight in humans and our project aims to find out exactly how and why this happens.
This study is investigating an autoimmune disease called lymphocytic hypophysitis, involving the master gland in the body, the pituitary. It often affects pregnant women and is under diagnosed. The aim of our study is to determine the cause of this disease and its unexplained link with pregnancy. We are also working on a new diagnostic test which will enable doctors to confirm the diagnosis by serological means. At present, invasive pituitary biopsy is needed. Whilst developing this new test, we ....This study is investigating an autoimmune disease called lymphocytic hypophysitis, involving the master gland in the body, the pituitary. It often affects pregnant women and is under diagnosed. The aim of our study is to determine the cause of this disease and its unexplained link with pregnancy. We are also working on a new diagnostic test which will enable doctors to confirm the diagnosis by serological means. At present, invasive pituitary biopsy is needed. Whilst developing this new test, we have identified three proteins and their genes. This information may have major implications for the study of pituitary gland function.Read moreRead less
Mechanisms Of Negative Feedback Regulation Of GnRH By Testosterone In Males
Funder
National Health and Medical Research Council
Funding Amount
$243,336.00
Summary
This project will improve our knowledge of the hormonal control of reproduction in males. The hormone testosterone, produced by the testes, acts on the brain to control the secretion of a substance called gonadotrophin releasing hormone (GnRH). GnRH acts on a small gland at the base of the brain to cause the production of hormones called gonadotrophins, that are essential for reproduction. These gonadotrophins act on the testes to ensure the production of sperm and other hormones, including test ....This project will improve our knowledge of the hormonal control of reproduction in males. The hormone testosterone, produced by the testes, acts on the brain to control the secretion of a substance called gonadotrophin releasing hormone (GnRH). GnRH acts on a small gland at the base of the brain to cause the production of hormones called gonadotrophins, that are essential for reproduction. These gonadotrophins act on the testes to ensure the production of sperm and other hormones, including testosterone. We plan to determine how testosterone acts on the brain to control GnRH secretion. To do this we will use male sheep and conduct a series of experiments designed to show where in the brain testosterone acts to ultimately affect the nerve cells that produce GnRH. Testosterone and similar compounds are increasingly being used as treatments for infertility, as a male contraception and misused as anabolic steroids. A thorough knowledge of how testosterone acts in the brain is necessary to improve treatments for reproductive disorders and ultimately to improve reproductive health in men.Read moreRead less
Characterisation Of A Novel Prostate-expressed Kallikrein-like Protease And Its Target Proteins
Funder
National Health and Medical Research Council
Funding Amount
$724,544.00
Summary
Prostate disease is common in most men in later life and can affect their quality of life adversely. The primary conditions are benign prostatic hyperplasia or BPH and prostate cancer. Symptoms of BPH affect between 50-70% of men over the age of 50 and prostate cancer is now the most common internal cancer diagnosed in men. More importantly, prostate cancer is the second most common cause of cancer deaths. We don't yet fully understand exactly how these diseases occur but the male sex hormones o ....Prostate disease is common in most men in later life and can affect their quality of life adversely. The primary conditions are benign prostatic hyperplasia or BPH and prostate cancer. Symptoms of BPH affect between 50-70% of men over the age of 50 and prostate cancer is now the most common internal cancer diagnosed in men. More importantly, prostate cancer is the second most common cause of cancer deaths. We don't yet fully understand exactly how these diseases occur but the male sex hormones or androgens are known to play an important role. Prostate specific antigen or PSA has become widely accepted as a useful tool in helping to detect prostate cancer and then monitoring the disease. PSA, which is regulated by androgens, is an enzyme that either activates or breaks down many proteins that are important in both the normal function of the prostate and in the development of cancer. PSA belongs to a family of enzymes called the kallikreins. We have recently discovered a new member of this family that, like PSA, is also found in the prostate. We have called this new enzyme, K6, as it is the sixth member of this family to be identified. So , this project is about characterising this new K6 enzyme, finding out if it is also found in the prostates of men with BPH and prostate cancer, whether it is also regulated by androgens and what sort of proteins it may activate in these diseases. We will also compare these findings with what we know about PSA in these diseases. From these studies, we will not only understand more about this K6 enzyme and how it might be important in the prostate but also how it relates to PSA. These findings may ultimately lead to some new approaches in the detection and treatment for BPH and prostate cancer.Read moreRead less
PRE CLINICAL TRIAL WITH FETAL PIG INSULIN-PRODUCING CELLS
Funder
National Health and Medical Research Council
Funding Amount
$292,416.00
Summary
If fetal pig cells are to be of value in normalizing blood glucose levels in diabetic people once transplanted, they must survive and mature after being grafted. The pre-clinical study proposed will examine several novel issues that are of direct relevance to future clinical trials. The diabetic pig will be used as recipient to address when the fetal cell matures after it is transplanted, how long the grafted cells will maintain normal blood glucose levels, and at which site it is most appropria ....If fetal pig cells are to be of value in normalizing blood glucose levels in diabetic people once transplanted, they must survive and mature after being grafted. The pre-clinical study proposed will examine several novel issues that are of direct relevance to future clinical trials. The diabetic pig will be used as recipient to address when the fetal cell matures after it is transplanted, how long the grafted cells will maintain normal blood glucose levels, and at which site it is most appropriate to transplant the cells. The baboon will be used as recipient to address the safety of transplanting the pig cells, especially from the pig endogenous retrovirus, and whether the immunosuppressive regime proposed for use in humans will prevent cellular rejection. The diabetic baboon will be used in the final experiment step to determine if normalization of blood glucose levels can be achieved in this xenografted animal just as it can in the diabetic pig.Read moreRead less
Mechanisms Of Hypoglycaemic Damage In Developing Brain- A Protective Role For The Insulin-like Growth Factor System
Funder
National Health and Medical Research Council
Funding Amount
$408,055.00
Summary
The developing brain in the newborn infant or young child is vulnerable to many damaging influences. It is highly dependent on its essential fuel, glucose. Hypoglycemia, or lack of glucose availability, is therefore among the most damaging insults to the young brain, potentially leading to learning difficulties, developmental delay, cerebral palsy or epilepsy. Babies born premature or very small are at risk, as are those exposed to excessive insulin, such as infants of diabetic mothers. Children ....The developing brain in the newborn infant or young child is vulnerable to many damaging influences. It is highly dependent on its essential fuel, glucose. Hypoglycemia, or lack of glucose availability, is therefore among the most damaging insults to the young brain, potentially leading to learning difficulties, developmental delay, cerebral palsy or epilepsy. Babies born premature or very small are at risk, as are those exposed to excessive insulin, such as infants of diabetic mothers. Children with diabetes are also at risk, when their therapy with insulin may at times be excessive, leading to hypoglycaemia and impaired glucose availability for the brain. This proposal is examining at the cellular level the mechanisms involved in loss of brain cells in the face of glucose starvation in these various conditions. We are using several in vitro models where we can grow segments of developing mouse brain or human nerve cells in a dish, compared to studies with mice subjected to low blood glucose (hypoglycemia). After establishing that our laboratory models are representative of the whole animal, we will explore the cellular mechanisms involved in neuronal death following hypoglycaemia, particularly the interaction between the insulin-like growth factor (IGF) and other cell survival genes. We will also examine the possibility that treatment with IGF will reduce the loss of nerves in the brain after an episode of hypoglycemia. This may offer new and effective early treatment for this damaging brain injury in both newborn babies and children with insulin-dependent diabetes.Read moreRead less