This project will test the proposal that rising follicle-stimulating hormone (FSH) levels in ageing females directly accelerate reproductive failure and bone loss , major public health issues due to delayed childbearing and our rising ageing population. We have developed a unique mouse model with elevated FSH levels that cause premature female infertility. We will now use this model to determine the direct effects of high FSH upon ovarian and uterine function, as well as bone loss with age.
Investigation Of The Genetic Basis Of Insulin Hypersecretion In A Mouse Model Of Pancreatic Islet Failure
Funder
National Health and Medical Research Council
Funding Amount
$406,980.00
Summary
Type 2 diabetes is a chronic disease that is associated with blindness, kidney failure, heart attacks and stroke and these are secondary to high blood sugar levels. Thus, determining the cause of high blood sugar levels in type 2 diabetes will lead to better management of the disease and ease the financial burden on the public health system. High blood sugar in type 2 diabetes results from the inability of the body to secrete enough insulin. Insulin is the main hormone that lowers blood sugar le ....Type 2 diabetes is a chronic disease that is associated with blindness, kidney failure, heart attacks and stroke and these are secondary to high blood sugar levels. Thus, determining the cause of high blood sugar levels in type 2 diabetes will lead to better management of the disease and ease the financial burden on the public health system. High blood sugar in type 2 diabetes results from the inability of the body to secrete enough insulin. Insulin is the main hormone that lowers blood sugar levels and is produced by the pancreas. The reason for reduced insulin secretion in type 2 diabetes is not known. Paradoxically, it has been shown that some people who are at an increased risk of developing diabetes (eg people with obesity or a family history of diabetes) secrete more insulin than normal. It is not clear why this is, but a few studies have suggested that reducing insulin secretion in these circumstances can protect the pancreas and preserve its ability to secrete the appropriate amount of insulin. The DBA-2 is a mouse strain that like humans with type 2 diabetes, its pancreas can also fail to secrete the appropriate amount of insulin and under these circumstances becomes diabetic. Furthermore our laboratory has generated evidence that shows that like people who are at risk of diabetes, DBA-2 mice in fact secrete more insulin prior to becoming diabetic. Whether the cause of this increased insulin secretion is linked to the eventual reduction of secretion is not known. The aim of this study is to identify the gene that causes increased insulin secretion in the DBA-2 mouse. Furthermore, genetically manipulated animals will be produced that contain only this gene to determine its effect on insulin secretion. Should the identification of this gene be related to the eventual failure of the pancreas to secrete enough insulin, then it would provide a target for drug therapy to correct insulin levels and therefore reduce blood sugar levels.Read moreRead less
The Mechanisms Of The Anabolic Actions Of Androgens In Bone.
Funder
National Health and Medical Research Council
Funding Amount
$470,960.00
Summary
Androgens (male sex hormones) are one of the few agents that increase bone formation. Androgens act by binding to a specific protein, the androgen receptor (AR). To understand exactly how androgens increase bone formation, we will study mice in which the AR is inactivated only in bone forming cells at specific stages of their development. Understanding the way in which androgens act on bone to increase size and strength will be of great benefit in the design of new treatments for osteoporosis.
The Pathogenesis Of Motor Neuron Degeneration Caused By A Triplet Repeat Expansion In The Androgen Receptor Gene.
Funder
National Health and Medical Research Council
Funding Amount
$284,748.00
Summary
Male sex hormones, or androgens, work by binding to a specific receptor, known as the androgen receptor. Androgens have an important and yet poorly understood role in nerve function. Our research is investigating how a genetic mutation in the androgen receptor causes Kennedy?s disease. This is a rare disease, affecting adult males, which causes nerves to die. The nerves which are affected are those supplying our muscles, called motor neurons. This leads to muscle wasting in the face and body. Ot ....Male sex hormones, or androgens, work by binding to a specific receptor, known as the androgen receptor. Androgens have an important and yet poorly understood role in nerve function. Our research is investigating how a genetic mutation in the androgen receptor causes Kennedy?s disease. This is a rare disease, affecting adult males, which causes nerves to die. The nerves which are affected are those supplying our muscles, called motor neurons. This leads to muscle wasting in the face and body. Other symptoms include testicular wasting, reduced fertility and breast tissue enlargement. It is currently not known what causes motor nerves to degenerate in Kennedy?s disease. We are endeavouring to investigate the cause of Kennedy?s disease via the generation of a transgenic mouse carrying this mutation. It is only through a studying transgenic mouse affected by this disease can we begin to understand what is happening to nerves to cause them to die, and importantly, how can we prevent them from dying. These studies will also provide crucial information on the effects of sex hormones on nerves. As there is currently no treatment for Kennedy?s disease, an aim of this project is to investigate how we can treat this disease. This will be the first time that we can systemically test potential treatments and work toward preventing the degeneration of these nerves. Kennedy?s disease is related to a number of other neurodegenerative diseases including Huntington?s disease, which are caused by similar genetic mutations. All of these diseases are caused by degeneration of specific nerve cells. Evidence suggests that there may be similar mechanisms involved in all of these diseases. The results of this study will therefore help us to understand a range of diseases and may eventually lead to the development of therapeutic strategies to prevent their debilitating effects.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