Determinants Of Insulin-like Growth Factor (IGF) Binding And Biological Actions Of IGF Binding Protein-6
Funder
National Health and Medical Research Council
Funding Amount
$399,750.00
Summary
Proteins are complex structures usually consisting of a number of distinct regions. Each of these regions may serve different roles. Insulin-like growth factors (IGFs) are important proteins involved in regulating the growth and other properties of cells. The actions of IGFs are in turn regulated by a family of binding proteins (IGFBPs). The aim of this project is to determine the range of actions of one of these IGFBPs and which parts of this IGFBP are involved in these actions. This may lead t ....Proteins are complex structures usually consisting of a number of distinct regions. Each of these regions may serve different roles. Insulin-like growth factors (IGFs) are important proteins involved in regulating the growth and other properties of cells. The actions of IGFs are in turn regulated by a family of binding proteins (IGFBPs). The aim of this project is to determine the range of actions of one of these IGFBPs and which parts of this IGFBP are involved in these actions. This may lead to new treatments for diseases in which cell growth is disturbed e.g. cancer and diabetes.Read moreRead less
Pathways Involved In The Insulin-like Growth Factor (IGF)-independent Actions Of IGF Binding Protein-6
Funder
National Health and Medical Research Council
Funding Amount
$550,725.00
Summary
Insulin-like growth factors (IGFs) are important proteins that regulate growth. When not regulated properly, diseases such as cancer can occur. A family of IGF binding proteins regulates IGFs. IGFBPs may inhibit IGFs and we have shown that one of them, IGFBP-6, decreases growth of some experimental cancers. As well as regulating IGFs, some IGFBPs alter cell behaviour independently of IGFs, and we found that IGFBP-6 stimulates cell movement in this way. We will now determine how this happens.
They aim to create insulin-secreting B cells by identifying their progenitor cells and the moleculaes normally required for their development, in order to restore B-cell function in the people with type 1 diabetes. Mouse and human multipotent embryonic stem (ES) cells and fetal mouse panceas and adult pancreas duct cells will be used as sources of progenitor B cells. Comparative studies will provide a more complete picture of human B-cell ontogeny. Culture systems developed for ES cells-embryoid ....They aim to create insulin-secreting B cells by identifying their progenitor cells and the moleculaes normally required for their development, in order to restore B-cell function in the people with type 1 diabetes. Mouse and human multipotent embryonic stem (ES) cells and fetal mouse panceas and adult pancreas duct cells will be used as sources of progenitor B cells. Comparative studies will provide a more complete picture of human B-cell ontogeny. Culture systems developed for ES cells-embryoid bodies (EB) - EB-derived cells, fetal pancreas and adult pancreas duct cells, will be employed to screen for and identify novel growth-differentiation factors and to optimise parameters for creating B cells in vitro or (re) generating B cells in vivo. Genetic constructs allowing regulated expression of fluorescently-tagged marker genes and growth-transcription factors will be introduced into cultured cells or transgenic mice to enable progenitor B cells to be tracked and isolated. Progenitor B cells will be typed with panels of known novel markers molecules at the gene and protein level, and gene expression profiles of tissue yielding B cells will be analysed across time to reveal further candidate markers. Molecules and methods effective in mouse systems will be applied to human ES cell-derived or pancreatic duct cells. The capacity to progenitor cells or insulin-secreting cells to ameliorate diabetes when transplanted into the testis, under the kidney capsule or into the pancreas of mouse models would represent proof-of-concept. Functional B cells derived from human ERS cells or pancreas duct cells, or growth factors that regenerate B cells in vivo, could together with appropriate immunotherapy restore B-cell function in people with type 1 diabetes.Read moreRead less
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.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.
MALE OSTEOPOROSIS: A POPULATION-BASED STUDY IN GEELONG
Funder
National Health and Medical Research Council
Funding Amount
$432,645.00
Summary
Osteoporosis is a term used to indicate that bones have become thin and fragile. During the ageing process bone fragility increases and fractures occur more easily and more often. Fractures may also occur during normal daily activities, with fractures of the spine, forearm and hip being common. However, many other sites may fracture. This is a serious problem because fractures cause pain, disability and, sometimes, death. Although previously overshadowed by its effect in women, osteoporosis is i ....Osteoporosis is a term used to indicate that bones have become thin and fragile. During the ageing process bone fragility increases and fractures occur more easily and more often. Fractures may also occur during normal daily activities, with fractures of the spine, forearm and hip being common. However, many other sites may fracture. This is a serious problem because fractures cause pain, disability and, sometimes, death. Although previously overshadowed by its effect in women, osteoporosis is increasingly being recognised in men. In Australia, 39% of all fractures occur in men and prognosis for fracture in men is worse than in women. A consequence of increasing male longevity is that osteoporosis will affect a growing number of Australian men. It is anticipated that between 1996 and 2051, the number of men with fracture will double, with a 4-fold increase in the number of male hip fractures. Unless the problem of osteoporosis in men is addressed and effective interventions are implemented, the substantial health burden imposed by age-related fractures will continue to escalate. In this case-control study of fracture risk in men, men with fractures (cases) will be identified prospectively for 3 years from radiological reports. Controls will be selected concurrently, at random from electoral rolls. Anticipated number of cases and controls are 800 and 1400, respectively. Cases and controls will be characterised for risk factors for fracture: bone density and bone geometry will be measured, serum samples collected, and diet, lifestyle and medical history documented by questionnaire. The advantage of this type of data is that information from patients with fracture will be used to tell us about the risk of fracture in healthy, unaffected men and about the characteristics of the Australian male population at risk for fracture. The information can be used in decision making for the individual and in policy making for the whole population.Read moreRead less
Mechanisms Of Pro-atherogenic Effects Of Androgens In Human Vascular Cells
Funder
National Health and Medical Research Council
Funding Amount
$211,320.00
Summary
Atherosclerosis is the most important cardiovascular disease and is now the leading cause of death in Western societies. A major clue to the causality of the disease is the striking gender gap in its prevalence and severity. The gender gap in atherosclerotic cardiovascular disease may be due to genetic, lifestyle or hormonal differences between males and females. Of these, hormonal differences are the most amenable to therapeutic intervention. Accordingly, there has been a lot of interest in the ....Atherosclerosis is the most important cardiovascular disease and is now the leading cause of death in Western societies. A major clue to the causality of the disease is the striking gender gap in its prevalence and severity. The gender gap in atherosclerotic cardiovascular disease may be due to genetic, lifestyle or hormonal differences between males and females. Of these, hormonal differences are the most amenable to therapeutic intervention. Accordingly, there has been a lot of interest in the potential protective effects of estrogens but few have studied the role of androgens with sophisticated approaches to androgen physiology and pharmacology. Clues from epidemiological and our recent studies suggest that androgenic influences on atherosclerosis may involve positive and negative effects on atherogenesis but the mechanisms are not understood. We now propose a comprehensive approach to studying androgenic effects on vascular biology both to enhance knowledge as well as potentially opening new therapeutic options in selective androgen receptor modulation.Read moreRead less
The Role Of Renin-angiotensin And Growth Factors In Developmental And Pathological Neovascularization In The Retina
Funder
National Health and Medical Research Council
Funding Amount
$342,562.00
Summary
In the normal retina of newborn babies, the blood vessels in the inner layers are not fully formed. These vessels are probably stimulated to grow by a reduction in retinal oxygen, which initiates the production of growth agents in retinal cells. Once the new vessels are formed the oxygen level of the retina becomes normal, and both the growth agents and blood vessel growth are reduced. A prolonged reduction in oxygen levels in the retina can have serious consequences for vision. Indeed, in some ....In the normal retina of newborn babies, the blood vessels in the inner layers are not fully formed. These vessels are probably stimulated to grow by a reduction in retinal oxygen, which initiates the production of growth agents in retinal cells. Once the new vessels are formed the oxygen level of the retina becomes normal, and both the growth agents and blood vessel growth are reduced. A prolonged reduction in oxygen levels in the retina can have serious consequences for vision. Indeed, in some eye diseases new blood vessel growth is excessive and the vessels are not properly formed, which leads to hemorrhage and ultimately blindness. Such events occur when the oxygen environment of premature babies is reduced after placement in high oxygen incubators. Also, in long-term diabetes, the oxygen levels of the retina falls as the retinal vessels become damaged. To understand the events that cause new vessel growth in retinal development and disease requires identification of the growth agents and their location in the retina. Very recently it has been found that the growth agent renin-angiotensin is made in the retina, and that its blockade in diabetic patients slows the progression of new retinal vessel growth. Renin-angiotensin is likely to cause its growth effects by increasing the production of other retinal growth agents. This proposal will study the role of renin-angiotensin and other growth agents in the developing newborn rat retina and in eye diseases. This information may lead to a further understanding of how blood vessels form in the retinas of newborn babies, and the production of new treatments for eye diseases characterized by blood vessel growth in the retina.Read moreRead less