Secretion is an essential step in memory and learning, control of metabolism and reproduction and the functioning of most organs. Secretory dysfunction also underlies many diseases including type 2 diabetes. We plan experiments to test for a new model of control of insulin secretion.
The Effect Of Ghrelin, Leptin And Orexins On The Function Of Pituitary Somatotropes In Rat, Mouse And Human.
Funder
National Health and Medical Research Council
Funding Amount
$447,000.00
Summary
Malnutrition such as obesity or wasting syndrome is accompanied by GH deficiency. Three newly discovered metabolic regulatory hormones, leptin from fat tissue, ghrelin from stomach and orexins from hypothalamus, play important roles in regulating appetite, energy expenditure, and adiposity. Receptors for three metabolic regulatory hormones are all present in pituitary GH secreting cells (somatotropes) and accumulated laboratory data indicate a modification of GH secretion by three hormones. Cont ....Malnutrition such as obesity or wasting syndrome is accompanied by GH deficiency. Three newly discovered metabolic regulatory hormones, leptin from fat tissue, ghrelin from stomach and orexins from hypothalamus, play important roles in regulating appetite, energy expenditure, and adiposity. Receptors for three metabolic regulatory hormones are all present in pituitary GH secreting cells (somatotropes) and accumulated laboratory data indicate a modification of GH secretion by three hormones. Contradictory results have however been reported. Mechanisms of action of these three hormones are not clear and the interrelationship between metabolic regulatory hormones and intrinsic GH regulatory system is unknown. We propose to clarify this issue by investigating the effect of in vivo treatment of mice and in vitro treatment of cultured pituitary cells with leptin, ghrelin, and orexins. GH secretion, GH and GH-regulatory hormones' receptor synthesis in pituitary somatotropes will be measured. We will also use GH-GFP transgenic mice, in which somatotropes are specifically marked with green fluorescent signal, to study morphological change of somatotropes in mouse pituitary glands after in vivo treatment. By completing this project, we will be able (1) to clarify the physiological role of metabolic regulatory hormones in control of GH levels and (2) to clarify the pathological role of metabolic regulatory hormones in GH deficiency occurred in malnutritional conditions.Read moreRead less
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
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
Functional Modulation Of Ovine And Human Somatotropes By In Vitro Application Of Leptin
Funder
National Health and Medical Research Council
Funding Amount
$227,036.00
Summary
Obesity is a common disorder in developed countries and a prevalent condition which is often stigmatized. Actuarial data indicate that life expectancy is reduced when body-mass index (body mass in kg-square of the height in metres) is 20% or more above the ideal (obesity is >28% above ideal). Growth hormone (GH) from pituitary gland is the major anabolic hormone to increase muscle and reduce fat. A significant reduction in GH is found in obesity. Indeed, visceral fat mass is primary negative ....Obesity is a common disorder in developed countries and a prevalent condition which is often stigmatized. Actuarial data indicate that life expectancy is reduced when body-mass index (body mass in kg-square of the height in metres) is 20% or more above the ideal (obesity is >28% above ideal). Growth hormone (GH) from pituitary gland is the major anabolic hormone to increase muscle and reduce fat. A significant reduction in GH is found in obesity. Indeed, visceral fat mass is primary negative statistical determinant of GH secretion in middle age men and women. It is clear that the reduction in GH is due to a low sensitivity of GH cells to GH-releasing hormone (GHRH) from brain. It is therefore necessary to understand the change of pituitary GH cells in obesity. A recently identified, fat cell secreted, polypeptide (leptin) is demonstrated to reduce food intake and increase energy expenditure. Receptors for leptin have been found in pituitary gland, mainly in GH secreting cells. In our preliminary experiments, leptin reduces GH secretion by decreasing GHRH receptor synthesis. Meanwhile, this leptin treatment increased the receptors for GH-releasing peptide (GHRP), a synthetic peptide stimulating GH secretion. We aim to investigate the effect of leptin on cultured ovine and human GH cells by studying important cell functions including hormone and receptors synthesis, intracellular signaling molecules, membrane ion channels and cellular secreting machinery. The results will clarify the mechanism underlying GH deficiency in obese patients. We will also test the effect of synthetic GHRP in combination with leptin in vitro. The relationship between GHRP and leptin on the functional modification of GH cells will also be studied. It is likely to see that GHRP reduces the inhibitory effect of leptin on GH cells. This may end up an effective therapeutical use of GHRP (oral available) in the treatment of obesity.Read moreRead less
Hormonal Predictors Of Cardiovascular Outcomes And Mortality In Ageing Men: The Role Of Androgens And The IGF System.
Funder
National Health and Medical Research Council
Funding Amount
$125,035.00
Summary
As men age levels of testosterone and growth hormone fall while ill health increases. We do not know if low hormone levels directly cause heart disease. We will measure testosterone and IGF1, which reflects growth hormone, in 4,200 older men, and relate hormone levels to the future risk of ill health especially heart disease, stroke and large artery blockages. This will clarify whether low hormone levels increase risk of ill health, and the value of studies to test hormone therapy in older men.
Functional Analysis Of A Novel Genetic Mouse Model For Congenital Growth Hormone Deficiency
Funder
National Health and Medical Research Council
Funding Amount
$519,131.00
Summary
Pituitary Hormone deficiency is not uncommon and is associated with poor growth, metabolism and fertility. Some cases of this disorder arise due to genetic changes that compromise the ability of the pituitary gland to make or secrete growth hormone (GH). Using cutting-edge genomics technology, we have generated a new genetic mouse model of GH deficiency. The aim of this project is to understand the function of this novel GH _regulating gene in mice and in humans.
Identifying The Pathological Mechanism Of Polyalanine Expansion Mutations In The X-linked Hypopituitarism Gene SOX3
Funder
National Health and Medical Research Council
Funding Amount
$402,846.00
Summary
Mental retardation (MR) is a debilitating disorder which affects 1-3% of the population. In many cases, MR results from changes (mutations) in genes which regulate the development of the brain before birth. We are studying families with an inherited form of MR termed X-linked Hypopituitarism (XH) in which only boys are affected. In addition to intellectual disability, boys with XH also have poor pituitary function resulting in short stature and slow metabolism. In severe cases, where the pituita ....Mental retardation (MR) is a debilitating disorder which affects 1-3% of the population. In many cases, MR results from changes (mutations) in genes which regulate the development of the brain before birth. We are studying families with an inherited form of MR termed X-linked Hypopituitarism (XH) in which only boys are affected. In addition to intellectual disability, boys with XH also have poor pituitary function resulting in short stature and slow metabolism. In severe cases, where the pituitary has failed to form completely, these babies are extremely ill and in some instances do not survive. We have previously shown that XH is due to an unusual change in the SOX3 gene in which the number of consecutive alanine residues is increased above a critical threshold (polyalanine expansion mutations). Similar mutations have recently been identified in several other genes that also cause severe birth defects. However, little is currently known about how polyalanine expansion mutations cause these disorders. The overall aim of this proposal is generate a mouse model for this disorder. Analysis of these mice will help us to answer many unresolved questions about this disorder including: How does the mutant protein cause this disorder? Which parts of the brain and pituitary are affected and how is their function altered? How does the mutant protein affect other genes and proteins in the cell? Ultimately, we hope that this mouse model will help us to develop new and improved therapies for XH and other disorders that are caused by alanine expansion mutations.Read moreRead less