The Mechanism Of Growth Hormone Receptor Activation
Funder
National Health and Medical Research Council
Funding Amount
$679,500.00
Summary
Growth hormone GH excess or deficit results in considerably shortened lifespan. While cardiovascular disease is a major element in this mortality, GH status has also been linked to kidney disease and diabetic retinopathy. Importantly, GH produced locally in breast cells and prostate cells transform s these cells, creating cancers. We aim to define how GH activates its receptor, to facilitate a GH antagonist which results from understanding how GH activates its cell surface receptor.
Validating A New Model For Growth Hormone Receptor Activation
Funder
National Health and Medical Research Council
Funding Amount
$472,500.00
Summary
Growth hormone is an important hormone therapeutic for treating dwarfism. Recently, many new therapeutic applications for growth hormone have been discovered, particularly in relation to its anabolic actions. These include post surgery recovery, enhanced bone fracture healing, Crohns disease, dilated cardiomyopathy, infertility and ageing. The hormone exerts these actions through its receptor, which is a class1 cytokine receptor, similar to many receptors important in regulating immunity, inflam ....Growth hormone is an important hormone therapeutic for treating dwarfism. Recently, many new therapeutic applications for growth hormone have been discovered, particularly in relation to its anabolic actions. These include post surgery recovery, enhanced bone fracture healing, Crohns disease, dilated cardiomyopathy, infertility and ageing. The hormone exerts these actions through its receptor, which is a class1 cytokine receptor, similar to many receptors important in regulating immunity, inflammation, metabolism and cancers. In principle, if we can find out how the GH receptor works, this information would help in designing drugs to treat many immune and inflammatory disorders. With current NHMRC support we have developed a model which describes how GH activates the receptor at a molecular level. The model involves two pre-associated receptors at the cell surface binding to the hormone, with the result that the receptors are rotated relative to each other, and this brings the two JAK2 signalling units attached tothe receptor inside the cell into alignment, so they can activate each other. We can activate the receptor without hormone by artificially rotating it. This model is a prediction based on several techniques, but lacks proof of rotation. There are also a number of issues relating to the need for rigidity in the receptors, so the torque can be transmitted into the cell, since many believe there is no rigidity just above the membrane. We predict there is , but need to prove this. This information is vital for designing small orally active mimics of growth hormone, and for developing GH antagonists, likely to be useful for breast and colon cancer. Finally, we have evidence that the specificity of receptor signalling can be changed by mutating the outer part of the receptor (novel). We believe this can be used to change the activity spectrum of GH, hence decrease side effects, by developing analogs which activate one pathway or the other.Read moreRead less
Identifying Mechanisms Of Resistance To Novel Hormonal Agents In Patients With Castrate-resistant Prostate Cancer
Funder
National Health and Medical Research Council
Funding Amount
$420,004.00
Summary
I am a medical oncologist focused on prostate cancer, a disease which kills over 3000 Australian men every year. Recent studies have shown that new hormone treatments help men with advanced prostate cancer live longer. Unfortunately, while these drugs are effective when first started, prostate cancers eventually become resistant to them and start growing again. By looking at why these drugs stop working, I hope to find better treatments for Australian men with advanced prostate cancer.
Regulation Of Growth Hormone Action By Oestrogen And Selective Oestrogen Receptor Modulators
Funder
National Health and Medical Research Council
Funding Amount
$474,750.00
Summary
Growth hormone (GH) is essential for body growth and development. In adult life, it plays a key role in regulating the ratio of body fat to muscle, thus influencing health. Disruption of GH action decreases muscle mass and increases body fat. These changes lead to reduced muscle strength and fitness, and increase the risk of diabetes, hypertension and cardiovascular mortality. Our laboratory has reported that oestrogens taken orally blunt GH action and cause unfavourable changes in body fat and ....Growth hormone (GH) is essential for body growth and development. In adult life, it plays a key role in regulating the ratio of body fat to muscle, thus influencing health. Disruption of GH action decreases muscle mass and increases body fat. These changes lead to reduced muscle strength and fitness, and increase the risk of diabetes, hypertension and cardiovascular mortality. Our laboratory has reported that oestrogens taken orally blunt GH action and cause unfavourable changes in body fat and muscle. How this happens is not known. As oral oestrogens are widely used in our society, it is important to understand the basis of their impact on GH action. SERMs, or selective oestrogen receptor modulators, are a group of drugs used in the treatment of breast cancer and osteoporosis. These substances mimic oestrogen action in some tissues, and block oestrogen action in others. Whether SERMs interfere with GH action as oestrogens do have not been studied, but such knowledge would have therapeutic significance because of their widespread and long-term use. GH action is mediated by a protein, called the GH receptor, located on the surface of target tissues. We propose that oestrogens and SERMs alter the production and function of this protein to control GH action. Thereby, this project is designed to test, in cultured cells of human origin, how oestrogens and SERMs modulate abundance of the GH receptor and its ability to mediate GH action. This work is anticipated to gain novel insights into the interaction of GH with oestrogens and SERMs. This information may also be useful for the design of new drugs devoid of adverse effects on GH action, and hence would have potentially significant implications in women s health and disease.Read moreRead less
Enrichment, Differentiation And Functional Analysis Of Growth Hormone Progenitor Cells From The Adult Mouse Pituitary
Funder
National Health and Medical Research Council
Funding Amount
$469,500.00
Summary
Many important bodily functions including growth, metabolism, onset of puberty, fertility, lactation and the ability to cope with stress are controlled by hormones secreted by the pituitary gland. Consequently, insufficient hormone production by the pituitary gland (hypopituitarism) results in life-threatening conditions which are a significant clinical problem. Growth Hormone (GH) deficiency is the most common form of pituitary hormone deficiency, affecting 1:3,500 individuals. Currently, GH de ....Many important bodily functions including growth, metabolism, onset of puberty, fertility, lactation and the ability to cope with stress are controlled by hormones secreted by the pituitary gland. Consequently, insufficient hormone production by the pituitary gland (hypopituitarism) results in life-threatening conditions which are a significant clinical problem. Growth Hormone (GH) deficiency is the most common form of pituitary hormone deficiency, affecting 1:3,500 individuals. Currently, GH deficiency is treated by daily injections of growth hormone at a cost of $30,000 to $50,000 per patient per annum. However, even with daily injections and despite the cost, it is difficult to mimic the naturally fluctuating hormone levels in the body, resulting in incomplete growth rescue. Long term injections also have severe side effects that can lead to cardiovascular problems, abnormal bone density, diabetes and cancers of various types. To overcome the disadvantages of hormone therapy we are investigating a new cell replacement therapy to treat GH deficiency. This approach requires knowledge about the mechanism by which GH-secreting cells are generated and maintained in the adult pituitary. For the first time, we have isolated a type of progenitor (unspecialised) cell from adult mouse pituitary that is capable of dividing and generating GH-secreting cells. Our current research aims to further purify these cells and to show that they are capable of secreting GH in response to biologically relevant signals. In addition, we will test whether these cells can grow and develop into functional cells when introduced into mice. In particular, we will test whether the progenitor cells can rescue dwarfism using a mouse model of GH deficiency. This pioneering study will provide the first insight into the possibility of cell therapy for the pituitary, and may ultimately lead to the development of better therapies for patients with GH deficiency.Read moreRead less
Defining Mechanisms Of Androgen Receptor Action That Impede Breast Cancer Progression
Funder
National Health and Medical Research Council
Funding Amount
$770,619.00
Summary
Androgens (A), commonly considered male hormones, are present in women and may protect them from developing aggressive breast cancer by opposing the cancer-promoting effects of estrogen (E) hormones. We propose that a disturbance in the balance between A and E action in breast cancer worsens the disease and results in a poor outcome for afflicted women. We aim to define how A and E hormones interact in breast cancer, with a view to developing new ways to treat breast cancer and predict outcome.
Exercise Reverses Cognitive Decline In Aged Animals By Growth Hormone Stimulation Of Neurogenesis In The Hippocampus
Funder
National Health and Medical Research Council
Funding Amount
$696,409.00
Summary
The production of new neurons in the hippocampus plays a critical role in learning and memory. With increasing age, this production slows and is associated with cognitive decline. However the stem cells that make new neurons are still present, and we have discovered that exercise activates these cells, leading to renewed neuron production and reversal of cognitive decline. We will explore how this process is regulated in order to develop strategies to reduce cognitive decline in humans.
Pushing AR Toward Better Outcomes In Breast And Prostate Cancers
Funder
National Health and Medical Research Council
Funding Amount
$998,754.00
Summary
Breast and prostate cancers kill >6000 Australians each year. These cancers are strikingly similar, both driven by hormone receptors that have ‘gone bad’. Current therapies aim to eradicate the receptors. While often effective, therapeutic resistance is common and results in fatal disease. We aim to develop new, less toxic treatments that switch receptor behaviour from good to bad, without destroying them. This should improve quality of life, while preventing drug resistance and loss of lives ....Breast and prostate cancers kill >6000 Australians each year. These cancers are strikingly similar, both driven by hormone receptors that have ‘gone bad’. Current therapies aim to eradicate the receptors. While often effective, therapeutic resistance is common and results in fatal disease. We aim to develop new, less toxic treatments that switch receptor behaviour from good to bad, without destroying them. This should improve quality of life, while preventing drug resistance and loss of lives.Read moreRead less
The Role Of Adjuvant Zoledronic Acid In Locally Advanced Prostate Cancer
Funder
National Health and Medical Research Council
Funding Amount
$384,132.00
Summary
This project seeks to confirm the highly encouraging early findings from the RADAR prostate cancer trial so that the new treatments tested can be brought in to clinical practice. The trial involved 1071 men at 23 cancer treatment centres in ANZ who had developed extensive cancerous masses in their prostates but without evidence of spread. All received their trial treatments between 2003 and 2007. This project involves the collection and analysis of follow up information up until September 2017.