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
Genetic Programs Regulated By The Nuclear Hormone Receptor, LXR, In Muscle: Control Of Cholesterol And Lipid Metabolism
Funder
National Health and Medical Research Council
Funding Amount
$425,250.00
Summary
The heightened occurrence of cardiovascular disease has been linked to disorders in lipid metabolism. Obesity, insulin resistance, and atherosclerosis are prevalent diseases associated with these dyslipidemias. Lipid homeostasis is regulated by dietary intake, de novo synthesis and catabolism. Disorders of lipid metabolism are associated with cardiovascular disease, insulin resistance-diabetes, obesity and hypertension. Raised levels of serum TGs, and low high density lipoprotein (HDL) cholester ....The heightened occurrence of cardiovascular disease has been linked to disorders in lipid metabolism. Obesity, insulin resistance, and atherosclerosis are prevalent diseases associated with these dyslipidemias. Lipid homeostasis is regulated by dietary intake, de novo synthesis and catabolism. Disorders of lipid metabolism are associated with cardiovascular disease, insulin resistance-diabetes, obesity and hypertension. Raised levels of serum TGs, and low high density lipoprotein (HDL) cholesterol levels are characteristic of lipotoxic diseases. HDLs have a defensive role in the prevention of atherogenic dyslipidemia by mediating cholesterol efflux from peripheral tissues through the hormone -dependent ATP-binding cassette (ABC) transporters back to the liver for excretion and elimination. Agents that raise the levels of high density lipoprotein cholesterol (HDLc) through cholesterol efflux provide a pharmaceutical solution for the prevention of hypercholesterolemia, atherogenic and cardiovascular disease. These hormone dependent cholesterol and lipid effluxing proteins are regulated by a protein named LXR. Understanding the functional role of LXR in skeletal muscle, a peripheral tissue that accounts for 40% of total body weight is of paramount importance in understanding whole body cholesterol homeostasis and lipid metabolism. Furthermore, LXR and LXR target genes that facilitate cholesterol efflux and consequently raise HDLc levels are important pharmaceutical targets. Identification of novel LXR targets in skeletal muscle, which has a significant role in insulin sensitivity and the blood lipid profile provides an additional platform for therapeutic intervention.Read moreRead less
Genetic Programs Induced By The Nuclear Hormone Receptor PPARdelta In Muscle: Control Of Lipid And Energy Homeostasis
Funder
National Health and Medical Research Council
Funding Amount
$432,750.00
Summary
Lipid homeostasis is regulated by dietary intake, de novo synthesis and catabolism. Lipid disease is associated with hyperinsulinemia, and anomalous levels of the lipid triad, i.e. low HDL-cholesterol, high LDL-cholesterol and elevated triglycerides. Increased incidence of cardiovascular disease has been linked to dyslipidemias associated with diet and lifestyle. Diabetes, atherosclerosis, and obesity are comorbidities with these lipid disorders. HDLs have a defensive role in the prevention of d ....Lipid homeostasis is regulated by dietary intake, de novo synthesis and catabolism. Lipid disease is associated with hyperinsulinemia, and anomalous levels of the lipid triad, i.e. low HDL-cholesterol, high LDL-cholesterol and elevated triglycerides. Increased incidence of cardiovascular disease has been linked to dyslipidemias associated with diet and lifestyle. Diabetes, atherosclerosis, and obesity are comorbidities with these lipid disorders. HDLs have a defensive role in the prevention of dyslipidemia by mediating cholesterol efflux from tissues. In contrast, the LDLs accumulate in the arterial wall leading to atherosclerosis. Physiological maintenance of lipid homeostasis requires a dynamic balance between metabolic signalling cascades, diet, lifestyle etc. PPPARs are nuclear hormone receptors that function as fatty acid activated transcription factors that regulate lipid and cholesterol homeostasis. PPARs are bona fide targets for the development of therapeutic compounds useful in the treatment of lipid disorders. PPAR delta is abundantly expressed in skeletal muscle, a major mass peripheral tissue that accounts for ~40% of total body weight. Muscle is a major site of glucose metabolism and, fatty acid oxidation. Furthermore, it is an important regulator of cholesterol homeostasis and HDL levels. Consequently, it has a significant role in insulin sensitivity, the blood lipid profile and lipid metabolism. Understanding the functional role of PPAR delta in skeletal muscle, a peripheral tissue that accounts for 40% of total body weight is of paramount importance in understanding whole body lipid homeostasis. Understsanding these receptors may provide a pharmaceutical solution for the prevention of hyper-lipidemia--cholesterolemia, and atherogenic disease. Moreover, it may lead to the identification of agents that influence a major mass tissue in terms of lipid absorption, and increased fatty acid oxidation, and consequently normalize the blood lipid profile.Read moreRead less
Adrenocortical cancers have a poor prognosis. It is essential that patients with adrenocortical cancers be diagnosed early and accurately to enable the initiation of appropriate treatment. Current methods do not reliably differentiate benign adrenal tumours from adrenocortical cancers. The aim of my project is to identify molecular markers which can accurately distinguish benign adrenal tumours from adrenocortical cancers, allowing accurate diagnosis and institution of optimal therapy.
Role Of Liver Receptor Homologue-1 (LRH-1) In Male Germ Cells
Funder
National Health and Medical Research Council
Funding Amount
$224,250.00
Summary
Historically the steroid sex hormones - oestrogens and androgens - have been regarded as female- and male- specific sex hormones, respectively. Oestrogens are produced by the ovary and regulate female-specific processes such as ovulation and development of female sexual characteristics, whereas androgens are produced by the testis and regulate male-specific functions. However it is now clear that the distinction between oestrogen and androgen is not a sharp one. For example, we now know that oes ....Historically the steroid sex hormones - oestrogens and androgens - have been regarded as female- and male- specific sex hormones, respectively. Oestrogens are produced by the ovary and regulate female-specific processes such as ovulation and development of female sexual characteristics, whereas androgens are produced by the testis and regulate male-specific functions. However it is now clear that the distinction between oestrogen and androgen is not a sharp one. For example, we now know that oestrogens are produced within the testis and play a very important role in male fertility. Human males patients who are unable to synthesise oestrogens are infertile. Similarly, mice that cannot produce oestrogens are also infertile, due to a defect in sperm production. Oestrogens are therefore critical for normal male fertility, and reduced oestrogen production within the testis may be a significant cause of infertility which would be easily treatable in the clinic. The protein LRH-1 regulates oestrogen production in other tissues. This proposal aims to identify the role of LRH-1 in testicular oestrogen production by identifiying the genes regulated by LRH-1 and the proteins that interact with it in the testis. We also aim to study the structure of these proteins in infertile men. These studies will define new genes associated with male infertility and may lead to the development of more effective treatments for this common condition.Read moreRead less
An Examination Of The Contribution Of Visceral Adiposity To Insulin Resistance In Humans.
Funder
National Health and Medical Research Council
Funding Amount
$335,800.00
Summary
The worldwide epidemic of Type 2 diabetes is related to major nutritional and activity changes interacting with a genetic predisposition. The two key defects in Type 2 diabetes are a reduced response to insulin (insulin resistance) and relative failure of insulin production. Insulin resistance is the earliest defect and is closely associated with cardiovascular risk. Obesity generates insulin resistance, but intraabdominal (visceral) fat has particular importance. Visceral fat cells are differen ....The worldwide epidemic of Type 2 diabetes is related to major nutritional and activity changes interacting with a genetic predisposition. The two key defects in Type 2 diabetes are a reduced response to insulin (insulin resistance) and relative failure of insulin production. Insulin resistance is the earliest defect and is closely associated with cardiovascular risk. Obesity generates insulin resistance, but intraabdominal (visceral) fat has particular importance. Visceral fat cells are different to other fat cells; they are very metabolically active and 'spill out' fatty acids indiscriminately contributing to insulin resistance in liver and muscle; they also produce hormones which may modify the action of insulin. We will study people undergoing abdominal surgery. Participants will be (1) normal weight and sensitive to insulin, (2) abdominally overweight and insulin resistant, (3) insulin resistant with Type 2 diabetes. We will document abdominal fat, circulating lipid and hormone levels and insulin action. At surgery fat biopsies will be obtained from (a) inside the abdominal cavity, (b) the fat layer under the abdominal skin and (c) fat in the buttock. The activity of a large number of genes in the fat tissue will be assessed in 8 subjects using DNA array (4 each from Groups 1 and 2). Then a small number of genes will be selected on the basis of different activity in visceral fat from buttock fat, and between insulin sensitive and insulin resistant people. The activity of these genes will be determined in all subjects in the 3 groups. We anticipate identifying a few (perhaps 3) genes whose activity is closely associated with insulin resistance and will examine their capability to block insulin action in a series of animal and cellular studies. These studies should identify specific mechanisms by which visceral fat creates insulin resistance. This would be an important step towards prevention and improved medication for Type 2 diabetes.Read moreRead less
Progesterone Signalling In Normal And Malignant Breast Relies On Chromosomal Positioning Of Progesterone Receptor
Funder
National Health and Medical Research Council
Funding Amount
$569,346.00
Summary
The cell nucleus carries genetic information that directs cell function. The nucleus is organised into compartments, which are altered in breast cancer, leading to altered function. The ovarian hormone progesterone acts via a receptor, which clumps into foci in the nucleus when active. In cancers, this clumping is disrupted. In this project we will work out how these foci control cell function, and how this leads to the specific functions of progesterone in normal breast and breast cancers.
Significance And Mechanisms Of Relative Progesterone Receptor Isoform Expression In Normal And Malignant Target Tissues
Funder
National Health and Medical Research Council
Funding Amount
$737,248.00
Summary
The ovarian hormone progesterone has a pivotal role in normal female physiology, in the uterus and ovary; in the mammary gland and in the brain. Human progesterone receptor, through which progesterone exerts its physiological effects, is expressed as two receptor proteins (PRB and PRA). These are identical except that PRA is shorter than PRB and present knowledge supports a role for both proteins in normal physiology. PR is also expressed in breast cancers, where one of its roles may be to inhib ....The ovarian hormone progesterone has a pivotal role in normal female physiology, in the uterus and ovary; in the mammary gland and in the brain. Human progesterone receptor, through which progesterone exerts its physiological effects, is expressed as two receptor proteins (PRB and PRA). These are identical except that PRA is shorter than PRB and present knowledge supports a role for both proteins in normal physiology. PR is also expressed in breast cancers, where one of its roles may be to inhibit oestrogen action and thereby limit tumour growth. A tumour which lacks PR would lack this capacity and this may be clinically associated with poorer prognosis. We have shown that primary tumours lacking PR are more likely to progress to secondary sites and this may provide support for this possibility. In addition, we have shown that over-expression of one PR isoform in breast cancers can be as biologically significant as lack of PR: tumours expressing predominantly one isoform were associated with poorer prognosis features.This project is aimed at investigating how PRA and PRB exert their effects on the range of progesterone targets in normal and malignant tissues. We will do this by determining whether PR isoforms are located in the same nuclear site in cells expressing one versus cells expressing both PR isoforms, to explore whether the proteins act separately in target cells. We will then ask whether the PR activity is different if only one isoform (PRA or PRB) is expressed versus both PRA and PRB. Another major issue which will be explored is the way in which the relative levels of PRA and PRB are controlled, and whether this is altered in breast cancers. Finally, we will explore the clinical significance of PR isoform expression. If achieved, the aims of this project will delineate the individual and combined action of - THIS FIELD WAS OVER 2000 CHARS, TEXT WAS REMOVED TO LODGE THE APPLICATION. A COPY OF THE ORIGINAL APPLICATION IS AVAILABLE FROM ARCHIVE-HARDCOPYRead moreRead less
Endocrine And Molecular Regulation Of Placental CRH Expression
Funder
National Health and Medical Research Council
Funding Amount
$466,980.00
Summary
Approximately 70% of infant death is associated with premature birth. Preterm birth occurs in 6-10% of pregnancies, and there has been no reduction in the rates of premature birth in the last 30 years. This is largely because we remain ignorant of how normal and abnormal birth is controlled. Understanding the physiology of human pregnancy is a critical step in the development of ways to detect and prevent preterm birth. Our group has demonstrated a link between production of a hormone (corticotr ....Approximately 70% of infant death is associated with premature birth. Preterm birth occurs in 6-10% of pregnancies, and there has been no reduction in the rates of premature birth in the last 30 years. This is largely because we remain ignorant of how normal and abnormal birth is controlled. Understanding the physiology of human pregnancy is a critical step in the development of ways to detect and prevent preterm birth. Our group has demonstrated a link between production of a hormone (corticotrophin releasing hormone, CRH) in the placenta and the length of time the baby is carried in the mother. In women who will deliver prematurely a rise in CRH occurs earlier in the pregnancy and more rapidly, while in women who deliver late the rise occurs more slowly. This work has given rise to the concept of a biological clock that determines the length of time the fetus will be carried by the mother before birth, and in which production of CRH in the placenta plays a central role. We have been studying how the CRH gene is controlled in placental cells. We have discovered some regions in the DNA of the CRH gene which have important roles in controlling how much CRH is made by the placenta. The experiments described in this research project will determine the molecular mechanisms that control the production of CRH in the human placenta. This will be done in two ways: (1) by examining the DNA sequences involved in controlling expression of the CRH gene and (2) by identifying the proteins that actually perform the regulating functions that result in either increased or decreased amounts of CRH being produced by the placenta. This important information will help us better understand how normal and abnormal birth is controlled, and from that knowledge new ways to detect and prevent premature birth can be invented.Read moreRead less
Characterisation Of The Molecular Mechanisms Mediating Aldosterone-induced Epithelial Electrolyte Transport
Funder
National Health and Medical Research Council
Funding Amount
$488,386.00
Summary
The steroid hormone aldosterone regulates blood pressure by controlling sodium retention. The importance of this role is underlined by the fact that all known mongenetic hypertensive conditions involve aldosterone or sodium retention. Aldosterone mediates this effect by activating an intracellular receptor protein that in turn switches on specific genes. This study seeks to identify the genes that are switched on (or off) by aldosterone and to characterise the region of the gene that interacts w ....The steroid hormone aldosterone regulates blood pressure by controlling sodium retention. The importance of this role is underlined by the fact that all known mongenetic hypertensive conditions involve aldosterone or sodium retention. Aldosterone mediates this effect by activating an intracellular receptor protein that in turn switches on specific genes. This study seeks to identify the genes that are switched on (or off) by aldosterone and to characterise the region of the gene that interacts with the receptor. Both cell and gene specific factors are thought to be important in defining the nature of this interaction; these factors will also be sought. This information will enhance our understanding of the basic biology of sodium transport in the colon and the kidney which in turn will clarify the role of aldosterone in high blood pressure, cardiac disease and perhaps even stress.Read moreRead less