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Field of Research : Nutritional science
Research Topic : IGF-binding proteins (IGFBP-2)
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    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.
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    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.
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    Funded Activity

    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.
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    Funded Activity

    Characterisation Of The IGF-independent And Dependent Actions Of IGF-binding-protein-6

    Funder
    National Health and Medical Research Council
    Funding Amount
    $39,121.00
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    Funded Activity

    Insulin-like Growth Factor Binding Protein-3 (IGFBP-3) Sensitivity And Signalling In Breast Cancer

    Funder
    National Health and Medical Research Council
    Funding Amount
    $414,343.00
    Summary
    The growth of all tissues in the body depends on many growth factors, hormones and other proteins which work together to control cell division. Some of these factors stimulate the division of the cells which make up the body tissues, and some inhibit it, so that a balance of these stimulators and inhibitors ensures that tissues do not grow too fast, or too large. The development of breast cancer and the growth of breast tumours is thought to be due to uncontrolled or faulty actions of the protei .... The growth of all tissues in the body depends on many growth factors, hormones and other proteins which work together to control cell division. Some of these factors stimulate the division of the cells which make up the body tissues, and some inhibit it, so that a balance of these stimulators and inhibitors ensures that tissues do not grow too fast, or too large. The development of breast cancer and the growth of breast tumours is thought to be due to uncontrolled or faulty actions of the proteins and hormones which regulate the way breast cells multiply. One protein which normally regulates the division of breast cells is IGFBP-3. We have found that in some breast cancer cells, IGFBP-3 is no longer able to inhibit cell division, and this may lead to tumour growth and invasion of other tissues. We are interested in finding out how IGFBP-3 normally controls breast cell proliferation, and why some breast cancers are resistant to IGFBP-3. To do this, we will use normal breast cells in culture to examine how IGFBP-3 interacts with other cellular factors to prevent cell division. We will then look at whether the breast cancer cells have changed so that they are no longer able to recognise IGFBP-3 as an inhibitory protein. This may be because of changes in the way IGFBP-3 binds to the breast cancer cell, or because of changes in the way it interacts with other proteins in the cell. Because IGFBP-3 is made by normal and breast cancer cells, we will also study whether the IGFBP-3 being made by breast cancer cells is normal, or if it changed in some way that makes it inactive. By understanding why some breast cancers are not inhibited by IGFBP-3, we will be able to design new and better methods of preventing, detecting and treating the growth of all breast tumours.
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    Funded Activity

    NOVEL MECHANISMS OF HORMONE ACTION

    Funder
    National Health and Medical Research Council
    Funding Amount
    $466,980.00
    Summary
    Steroid hormones, such as oestrogen and cortisol, act in the body by binding a family of proteins (nuclear receptors) that bind directly to the DNA to regulate genes. The mechanisms underlying this process are complex and involve recruitment of additional molecules or coactivators to improve efficiency. Recently a novel coactivator was identified termed SRA, which remarkably is never made into protein in cells, rather exerting its effects as a RNA. We have identified a novel family of proteins t .... Steroid hormones, such as oestrogen and cortisol, act in the body by binding a family of proteins (nuclear receptors) that bind directly to the DNA to regulate genes. The mechanisms underlying this process are complex and involve recruitment of additional molecules or coactivators to improve efficiency. Recently a novel coactivator was identified termed SRA, which remarkably is never made into protein in cells, rather exerting its effects as a RNA. We have identified a novel family of proteins that bind to SRA in cancer cells, and may well play a critical role in regulating how SRA modulates genes. This project seeks to understand how this family interacts with SRA, the functional effects on breast cancer cells, and the detailed 3-dimensional structure of the family members coupled with SRA. This work will provide novel insight into how SRA regulates steroid hormone action, and may create new potential avenues for developing therapeutics in breast cancer.
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    Funded Activity

    Role Of IGF Binding Protein-3 (IGFBP-3) And IGFBP-5 As Modulators Of Nuclear Hormone Signalling

    Funder
    National Health and Medical Research Council
    Funding Amount
    $465,750.00
    Summary
    The insulin-like growth factors are small proteins involved in the growth of most tissues. Their actions are regulated by binding to larger proteins (known as IGFBPs) in the bloodstream and outside the cell. However, some IGFBPs are also found inside cells, where they seem to carry out other functions. We believe that two of these binding proteins, IGFBP-3 and IGFBP-5, change the way cells respond to vitamin A and vitamin D. These two vitamins are important in cell growth and in the way certain .... The insulin-like growth factors are small proteins involved in the growth of most tissues. Their actions are regulated by binding to larger proteins (known as IGFBPs) in the bloodstream and outside the cell. However, some IGFBPs are also found inside cells, where they seem to carry out other functions. We believe that two of these binding proteins, IGFBP-3 and IGFBP-5, change the way cells respond to vitamin A and vitamin D. These two vitamins are important in cell growth and in the way certain cells perform specialised functions. In test-tube experiments, IGFBP-3 and IGFBP-5 interact directly with the receptors that regulate the effects of these hormones. If the same thing happens inside the cell, IGFBP-3 and IGFBP-5 could change the way these receptors respond to signals from outside the cell. We will investigate what effect these IGFBPs have in living cells and in whole animals and how this may relate to human disease. If we are able to understand how IGFBP-3 and IGFBP-5 affect the way cells respond to vitamin A and D, then we may be able to develop new ways to treat certain human diseases.
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    Funded Activity

    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.
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    Funded Activity

    Epigenetic Control In Type 2 Diabetes

    Funder
    National Health and Medical Research Council
    Funding Amount
    $75,250.00
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    Funded Activity

    Genetic Programs Induced By Growth Hormone

    Funder
    National Health and Medical Research Council
    Funding Amount
    $421,980.00
    Summary
    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.
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