Structural And Functional Investigation Into The Cooperation Of IGF And Vitronectin-binding Receptors In Cell Migration
Funder
National Health and Medical Research Council
Funding Amount
$239,250.00
Summary
Breast cancer is the most commonly diagnosed form of cancer in Australian women, accounting for 26% of diagnosed cancers and 21% of cancer deaths among women. One in fourteen Australian and one in nine women worldwide will develop breast cancer in their lifetime. Significantly, approximately one in four of those diagnosed will die from their disease. The primary factor that determines survival is early diagnosis and treatment. Indeed, the primary tumour itself rarely causes death. Rather, the di ....Breast cancer is the most commonly diagnosed form of cancer in Australian women, accounting for 26% of diagnosed cancers and 21% of cancer deaths among women. One in fourteen Australian and one in nine women worldwide will develop breast cancer in their lifetime. Significantly, approximately one in four of those diagnosed will die from their disease. The primary factor that determines survival is early diagnosis and treatment. Indeed, the primary tumour itself rarely causes death. Rather, the dissemination of tumour cells to remote sites and the establishment of secondary tumours in critical sites in the body is the major mechanism of mortality. An understanding of the processes that lead to the establishment of secondary tumour bodies and strategies to halt the spread of cancer beyond the primary site are therefore highly valuable. Two factors thought to be pivotal in breast cancer metastasis are altered interactions with the microenvironment surrounding cells and exposure to increased levels of hormones and growth factors, such as the insulin-like growth factors (IGFs). We have recently found that IGFs form complexes with a protein called vitronectin, found in the microenvironment, and these complexes can stimulate increased migration of breast cancer cells. This project will examine the interaction of IGF and VN in stimulating cell migration and in particular, aims to identify the genes involved in the enhanced cell migration. In addition we will examine how the IGF:vitronectin complexes form and how these in turn interact with receptors on the surface of the cell. The data obtained will provide critical fundamental information that is necessary to develop targeted therapies for the treatment and control of breast cancer.Read moreRead less
Reversal Of Diabetes In Pigs Using Liver-directed Gene Therapy
Funder
National Health and Medical Research Council
Funding Amount
$573,807.00
Summary
Type I diabetes mellitus is caused by the autoimmune destruction of the beta cells of the pancreas that secrete insulin. We have shown that we can cure diabetes in spontaneously diabetic mice by delivery of the insulin gene to the liver using a non-pathogenic viral delivery system. The study aims to repeat this work in pigs which have similar physiology to humans. If successful this would be proof-of-principle that we could theoretically control blood glucose levels in humans.
Growth hormone is responsible for normal postnatal growth, is an important metabolic regulator in starvation, and has many useful therapeutic applications, including forms of cardiac insufficiency, Crohns disease and, it is thought, amelioration of ageing. The means whereby GH brings about these changes are not known, although we do know a considerable amount about how the individual domains within the GH receptor signal. What we do not know is which genes are regulated by GH in these processes, ....Growth hormone is responsible for normal postnatal growth, is an important metabolic regulator in starvation, and has many useful therapeutic applications, including forms of cardiac insufficiency, Crohns disease and, it is thought, amelioration of ageing. The means whereby GH brings about these changes are not known, although we do know a considerable amount about how the individual domains within the GH receptor signal. What we do not know is which genes are regulated by GH in these processes, and how this will change the state of the cell. We propose here to use the new technique of gene arrays to uncover the programs, or groups of genes, which GH regulates to change important cellular processes. When used in conjunction with cells expressing GH receptor mutants which are unable to signal to defined pathways, we will be able to know which functional families genes are regulated, and how they are regulated. This information will enable us to know how GH regulates cell growth and metabolism, and therfore to understand what goes wrong when GH or its mediator, IGF-1 , are abnormal. We can also use this information to validate small molecules designed to mimic GH through activating its receptor, to be certain that they are acting in the same way as GH.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
Endocrine And Autocrine Regulation Of Breast Cancer Cell Growth By IGF Binding Protein-3 (IGFBP-3).
Funder
National Health and Medical Research Council
Funding Amount
$497,250.00
Summary
The insulin-like growth factor (IGF) system of growth factors and their regulatory proteins is essential for normal growth, but is also involved in a number of overgrowth disorders. Some clinical studies have shown that a high level of IGF-I in the blood increases the risk of breast cancer in some women, but if the protein which carries it in the circulation, IGFBP-3, is also high, the risk is reduced. It has therefore been suggested that IGFBP-3 may be useful in the treatment of breast cancer. ....The insulin-like growth factor (IGF) system of growth factors and their regulatory proteins is essential for normal growth, but is also involved in a number of overgrowth disorders. Some clinical studies have shown that a high level of IGF-I in the blood increases the risk of breast cancer in some women, but if the protein which carries it in the circulation, IGFBP-3, is also high, the risk is reduced. It has therefore been suggested that IGFBP-3 may be useful in the treatment of breast cancer. This is supported by laboratory studies showing that IGFBP-3 can inhibit cell division and stimulate cell death in many cell types, including breast cells. However, some cells are resistant to IGFBP-3 s inhibitory effects, and in some cases IGFBP-3 may stimulate cells to grow and divide. In fact, the amount of IGFBP-3 present in breast tumours is highest in the fastest growing, most malignant tumours, suggesting that IGFBP-3 may be stimulating their growth. Our laboratory data indicates that breast cancer cells which produce a high level of IGFBP-3 grow faster as tumours than cells which produce little or no IGFBP-3. We believe that this is because IGFBP-3 interacts with another hormone system which is involved in rapid tissue growth, the EGF system, and increases its ability to stimulate breast cells to divide. These observations raise a number of important questions: how does IGFBP-3 interact with the EGF system to stimulate tumour growth; does IGFBP-3 from the blood promote the growth of EGF-sensitive tumours; and can the interaction between IGFBP-3 and the EGF system be abolished, or switched from growth stimulatory to growth inhibitory, thus inhibiting tumour growth. Answering these questions will provide important new information regarding IGFBP-3 s stimulatory and inhibitory actions, and the role of endocrine IGFBP-3 in tumour growth, and have the potential to lead to the development of novel therapies involving IGFBP-3 for the treatment of overgrowth disorders.Read moreRead less
Epidermal Growth Control In Psoriasis And Normal Skin
Funder
National Health and Medical Research Council
Funding Amount
$451,980.00
Summary
Our skin protects us from damage, dehydration, infection and harmful UV radiation. At the same time, we expect it to remain healthy, smooth and looking good. How the skin, and more particularly its upper layer, the epidermis, adapts to all these requirements is a complex problem yet to be fully understood. This question forms the basis of our project proposal. The epidermis is a continuously self-renewing tissue, in which cells have an average life of 30 days before they are invisibly shed to th ....Our skin protects us from damage, dehydration, infection and harmful UV radiation. At the same time, we expect it to remain healthy, smooth and looking good. How the skin, and more particularly its upper layer, the epidermis, adapts to all these requirements is a complex problem yet to be fully understood. This question forms the basis of our project proposal. The epidermis is a continuously self-renewing tissue, in which cells have an average life of 30 days before they are invisibly shed to the outside. In normal states and when responding to injury or disease, this cell turnover speed can be finely tuned, for example accelerated in the case of a healing wound. In contrast, if damaged by the sun, epidermal cells undergo a form of cell suicide (apoptosis) to prevent tumours forming from cells with damaged genes. This changing turnover speed is controlled by a series of growth factors, or cytokines. Insulin-like growth factor-I (IGF-I) is a unique cytokine that can control both cell turnover rate, and cell death. We aim to uncover the complex biochemical interactions that allow the epidermal IGF-I system to achieve this seemingly contradictory task. This study is important because when the epidermis loses the ability to finely tune its turnover speed, ulcers, sun damage, the common skin disorder psoriasis, or worse still, skin tumours, arise. This project explores ways of manipulating the IGF-I system to prevent this, and builds on some technology developed by the research group that has already proven effective in the control of psoriasis. The project also promises to discover undiscovered growth regulators that could be used in new gene therapies for skin overgrowth diseases.Read moreRead less
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
Regulation And Effect Of The Growth Hormone, IGF-I, And IGF-Binding Protein Response To Acute Exercise
Funder
National Health and Medical Research Council
Funding Amount
$367,197.00
Summary
The body's ability to respond to physiological stress is vital to survival. This series of studies aims to examine the hormonal responses to physical exercise. In studies recently completed to determine how to detect Growth Hormone (GH) abuse in the Olympics, we have discovered a new system of hormones that respond to exercise. These Insulin-like Growth Factors (IGF) and their IGF-Binding Proteins (IGF-BP) are normally controlled by GH. The IGF-IGF-BP system normally acts to control of many cell ....The body's ability to respond to physiological stress is vital to survival. This series of studies aims to examine the hormonal responses to physical exercise. In studies recently completed to determine how to detect Growth Hormone (GH) abuse in the Olympics, we have discovered a new system of hormones that respond to exercise. These Insulin-like Growth Factors (IGF) and their IGF-Binding Proteins (IGF-BP) are normally controlled by GH. The IGF-IGF-BP system normally acts to control of many cellular and organ functions in many different tissues of the body. For example they stimulate protein accumulation and muscle growth, and have actions to control blood glucose in conditions like diabetes. Little is known about what regulates the production of the IGF and IGF-BPs in response to physical exercise. We aim to examine whether GH, either as an acute pulse as occurs naturally, or a direct effect of exercise that is not GH-mediated, is responsible for the increase in IGF and IGFBPs. This may uncover a new means of controlling this powerful hormonal system. In addition, we will examine whether GH or IGF-I, alone and together, influence the body's ability to respond to the stress of exercise (e.g., controlling fuel use, cardiovascular and kidney responses). Such information will allow greater understanding of this important hormonal system, so that in novel therapies may be developed for conditions such as normal ageing, the wasting states that accompany severe surgical or infectious stress, or conditions with abnormal blood glucose regulation such as diabetes. In addition, this information will permit greater sophistication in the detection of GH and related compounds in elite athletes. Unfortunately, GH is also being abused by non-elite athletes and high-school children. We believe our efforts will asist in the detection and prevention of these more general societal health issues.Read moreRead less