Regulation And Functional Roles Of ADAM 10 Protease In Prostate Cancer.
Funder
National Health and Medical Research Council
Funding Amount
$465,750.00
Summary
Prostate cancer is the second most common cause of cancer death among western males. Most deaths from prostate cancer are due to the development of secondary tumours (metastases) in other body organs. Metastasis involves actions of enzymes, (called metalloproteinases) which can break down the tissue structure surrounding tumour cells, and actions of a family of proteins (called integrins)that control how cells stick to each other or to other tissue components. Both these actions allow tumour cel ....Prostate cancer is the second most common cause of cancer death among western males. Most deaths from prostate cancer are due to the development of secondary tumours (metastases) in other body organs. Metastasis involves actions of enzymes, (called metalloproteinases) which can break down the tissue structure surrounding tumour cells, and actions of a family of proteins (called integrins)that control how cells stick to each other or to other tissue components. Both these actions allow tumour cells to break free from their original tissue positions, walk through surrounding tissue and deposit themselves at distant sites to form a secondary tumour. In this research we are looking at a protein, called ADAM-10, which belongs to a family of proteases, the ADAMs, which contain both A Disintegrin And Metalloprotease activity, hence their name. Our data suggest ADAM-10 is produced in large quantities by prostate cancer cells but can be differently located within these cells it sits on the outer membrane of normal or benign prostate glands but re-locates to the cell nucleus in high grade prostate cancer cells. We have also identified ADAM-10 protein in small membrane fragments that are commonly shed from prostate cancer cells. Preliminary evidence suggests that levels of ADAM-10 in each of these locations is regulated by growth factors and-or the male sex hormone, androgen, key hormones involved in prostate cancer growth and progression. We do not yet know what actions ADAM-10 has when it occurs in these different locations but believe the membrane form will be involved in metastasis, with the nuclear form being involved in regulating events within the nucleus, the control centre for the cell. This grant application aims to build on our novel observations and investigate the underlying mechanisms of ADAM-10 hormonal regulation and function. If proven, these issues may be important for the development, progression and future treatment of prostate cancer.Read 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
NR1F (ROR) Nuclear Hormone Receptors And Metabolism: Insights Into The Control Of Lipid Homeostasis.
Funder
National Health and Medical Research Council
Funding Amount
$581,892.00
Summary
ROR is a member of a gene family, that regulates reproduction, endocrine physiology, and metabolism, and are important in human health. ROR function remains illusive. However, it is expressed in liver, fat and muscle, tissues that (i) modulate blood lipids, insulin sensitivity and energy balance, and (ii) have an important role in diabetes and obesity. Understanding ROR function in metabolism provides the opportunity for the discovery of new pathways that ameliorate metabolic disease.
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
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
Osteoclasts (OC) are large multinucleated cells present in bone that are responsible for bone resorption. The renewal of bone and bone growth are regulated by the opposing actions of OCs and osteoblasts, cells that form new bone. Together, with other accessory cells in the bone marrow, these constitute 'bone-forming units' (BFU). Excess production or over-activation of OCs in the BFU leads to common bone conditions such as osteoporosis, Paget's disease and the bone lysis caused by bone cancers. ....Osteoclasts (OC) are large multinucleated cells present in bone that are responsible for bone resorption. The renewal of bone and bone growth are regulated by the opposing actions of OCs and osteoblasts, cells that form new bone. Together, with other accessory cells in the bone marrow, these constitute 'bone-forming units' (BFU). Excess production or over-activation of OCs in the BFU leads to common bone conditions such as osteoporosis, Paget's disease and the bone lysis caused by bone cancers. Osteoporosis causes a great deal of pain and disability and it alone costs the Australian taxpayers more than $400 million per year. OCs are formed from white blood cells that are present in the bone marrow and the blood. The recent discovery of a family of new factors that control the formation of OCs has enabled the generation of human OCs in the laboratory so now we can investigate the genes that control the process of conversion of white blood cells to OCs. An important advance in this project involves the use of cord blood that contains stem cells. These very na ve cells will enable us to study the very earliest genes that control differentiation of precursors to OC. We have found a number of genes that are regulated by these new bone-forming factors. In white blood cells the activation of particular genes can regulate OC formation. One example is vitamin D-upregulated gene, VDUP. This gene is of particular interest as it causes inhibition of the mechanism that leads to OC formation in the bone. Obviously, the ability to control a 'switch' that regulates OC formation may enable us to control the progress of bone loss in diseases such as osteoporosis. In this project, we intend to investigate how and why the genes that lead to OC formation are regulated and what influence the various bone cell factors have on the formation of bone-resorbing OCs. These studies will lead to the development of treatments for osteoporosis and other bone diseases.Read moreRead less
Lipid Metabolism In The Aromatase Knock-out Mouse (ArKO)
Funder
National Health and Medical Research Council
Funding Amount
$408,055.00
Summary
Studies of humans with natural mutations in aromatase, the enzyme responsible for oestrogen biosynthesis, have revealed a number of unexpected roles for oestrogens in both males and females. These discoveries even challenge the definitions of oestrogens and androgens as we now know them. We have created a mouse model of oestrogen insufficiency by targetted disruption of the aromatase gene. These mice display a number of age dependent phenotypes including both male and female infertility, undermi ....Studies of humans with natural mutations in aromatase, the enzyme responsible for oestrogen biosynthesis, have revealed a number of unexpected roles for oestrogens in both males and females. These discoveries even challenge the definitions of oestrogens and androgens as we now know them. We have created a mouse model of oestrogen insufficiency by targetted disruption of the aromatase gene. These mice display a number of age dependent phenotypes including both male and female infertility, undermineralisation of the bones, intra-abdominal obesity, hypercholesterolaemia and insulin resistance. We are addressing the mechanisms of all of those phenotypes but in the present application we focus on the abnormalities in lipid metabolism. Thus we will seek to understand the increase in adiposity by examining the role of oestrogen in lipid synthesis, oxidation and breakdown in adipose tissue from intra-abdominal sites. We will also examine the role that oestrogen plays in cholesterol uptake, synthesis and catabolism by the liver as well as fatty acid synthesis and oxidation by the liver. These studies will be correlated with whole body parameters such as feeding behaviour, physical activity, energy expenditure, glucose and fat oxidation rates. We will also examine the effect of feeding a high cholesterol or a high fat diet on lipid metabolism in the oestrogen deficient animals, and we will determine the effect of oestradiol and isoflavone replacement on the phenotype. In this way we aim to reach a better understanding of the multiplicity of roles that oestrogens play in the regulation of lipid and cholesterol metabolism in both males and females. The results of such studies will be the development of better strategies to deal with pathologies resulting from disturbances in cholesterol and lipid metabolism.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
Role Of The Nuclear Growth Hormone Receptor In Cell Proliferation And Function
Funder
National Health and Medical Research Council
Funding Amount
$477,750.00
Summary
In addition to final height, growth hormone regulates many tissues in the body, and through these, regulates metabolism, body composition, vitality and aspects of ageing. However, there is some evidence that GH can also promote cancer, notably colon and blood cell cancers. Our discovery of the receptor for growth hormone in the cell nucleus, notably in many cancers, has led us to investigate the role of the nuclear GH receptor. We have found that targeting this receptor to the nucleus allows the ....In addition to final height, growth hormone regulates many tissues in the body, and through these, regulates metabolism, body composition, vitality and aspects of ageing. However, there is some evidence that GH can also promote cancer, notably colon and blood cell cancers. Our discovery of the receptor for growth hormone in the cell nucleus, notably in many cancers, has led us to investigate the role of the nuclear GH receptor. We have found that targeting this receptor to the nucleus allows the cell to divide without the need for the normal factors which initiate cell division and survival. We have also found that a part of the GH receptor acts as a gene activator, and have identified some of the nuclear proteins which bind to the receptor and make this so. This proposal aims to establish the link between the nuclear GH receptor and cell division, both mechanistically, and in live animals. We also plan to establish if nuclear localizing the receptor artificially results in cancer formation. The outcome would provide an index of risk from current GH therapy, and could lead to a new cancer therapy.Read moreRead less