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
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
Focimatrix Regulation Of Sex Steroid Hormones In The Ovary
Funder
National Health and Medical Research Council
Funding Amount
$291,309.00
Summary
Sex steroid hormones (e.g. oestrogen and testosterone), are important to male and female health. In the ovarian follicle I identified a novel form of extracellular matrix (focimatrix) which develops in the ovary before the synthetic enzymes needed for sex steroids are present. Using evidence from other tissues, I developed ideas on how this matrix regulates the enzymes for hormone synthesis. I will examine a mechanism by which focimatrix could directly affect steroid hormone production.
Of Mice And Men: Assessing Dietary Proteins Role On Appetite Regulation, Obesity And Cardiovascular Risk
Funder
National Health and Medical Research Council
Funding Amount
$86,521.00
Summary
While the challenge of understanding and managing the global obesity epidemic is well recognised, the role that nutrition plays is more complex than at first glance. Dietary protein may be of central importance in managing weight and small changes in protein consumption may lead to large changes in energy intake and weight. We propose to look at the effects of dietary protein on appetite, its hormonal regulation, and on the risk of developing metabolic diseases such as diabetes.
The Role Of Liver Fructose-1,6-phosphatase (FBPase) In Body Weight Regulation
Funder
National Health and Medical Research Council
Funding Amount
$494,718.00
Summary
We have shown that fructose-1,6-bisphosphatase (FBPase), an enzyme important in producing sugar from the liver and one that is connected to Type 2 diabetes, does not cause an increase in sugar production when there is more of the enzyme in mouse livers. It does, however, lower both body weight and the amount of food the mice consume. We therefore hypothesise that liver FBPase is important in controlling body weight in humans and our project aims to find out exactly how and why this happens.
Regulation And Effect Of The Growth Hormone, IGF-I, And IGF-Binding Protein Response To Acute Exercise
Funder
National Health and Medical Research Council
Funding Amount
$367,197.00
Summary
The body's ability to respond to physiological stress is vital to survival. This series of studies aims to examine the hormonal responses to physical exercise. In studies recently completed to determine how to detect Growth Hormone (GH) abuse in the Olympics, we have discovered a new system of hormones that respond to exercise. These Insulin-like Growth Factors (IGF) and their IGF-Binding Proteins (IGF-BP) are normally controlled by GH. The IGF-IGF-BP system normally acts to control of many cell ....The body's ability to respond to physiological stress is vital to survival. This series of studies aims to examine the hormonal responses to physical exercise. In studies recently completed to determine how to detect Growth Hormone (GH) abuse in the Olympics, we have discovered a new system of hormones that respond to exercise. These Insulin-like Growth Factors (IGF) and their IGF-Binding Proteins (IGF-BP) are normally controlled by GH. The IGF-IGF-BP system normally acts to control of many cellular and organ functions in many different tissues of the body. For example they stimulate protein accumulation and muscle growth, and have actions to control blood glucose in conditions like diabetes. Little is known about what regulates the production of the IGF and IGF-BPs in response to physical exercise. We aim to examine whether GH, either as an acute pulse as occurs naturally, or a direct effect of exercise that is not GH-mediated, is responsible for the increase in IGF and IGFBPs. This may uncover a new means of controlling this powerful hormonal system. In addition, we will examine whether GH or IGF-I, alone and together, influence the body's ability to respond to the stress of exercise (e.g., controlling fuel use, cardiovascular and kidney responses). Such information will allow greater understanding of this important hormonal system, so that in novel therapies may be developed for conditions such as normal ageing, the wasting states that accompany severe surgical or infectious stress, or conditions with abnormal blood glucose regulation such as diabetes. In addition, this information will permit greater sophistication in the detection of GH and related compounds in elite athletes. Unfortunately, GH is also being abused by non-elite athletes and high-school children. We believe our efforts will asist in the detection and prevention of these more general societal health issues.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
The Functional Roles Of ADAMs In The Regulation Of Embryo Implantation.
Funder
National Health and Medical Research Council
Funding Amount
$211,527.00
Summary
The initiation of pregnancy in humans and rodents hinges upon the ability of the embryo to attach to the wall of the uterus and invade into the uterine tissue. This process of embryo implantation is tightly regulated and depends on the secretion of enzymes and regulators of these enzymes. A newly identified family of enzymes which might be important in this process is the ADAMs family. These enzymes have the potential to facilitate both cell attachment and cell invasion and also to activate othe ....The initiation of pregnancy in humans and rodents hinges upon the ability of the embryo to attach to the wall of the uterus and invade into the uterine tissue. This process of embryo implantation is tightly regulated and depends on the secretion of enzymes and regulators of these enzymes. A newly identified family of enzymes which might be important in this process is the ADAMs family. These enzymes have the potential to facilitate both cell attachment and cell invasion and also to activate other enzymes and growth factors. Recent studies in our laboratory have shown the ADAMs to be expressed both at the most invasive time of implantation and when invasion is being down-regulated. This project will examine the role of the ADAMs in embryo implantation facilitating attachment and invasion into the uterus by acting enzymatically on the uterine tissue and by activating other enzymes. It will also determine the role of ADAMs in down-regulating invasion potentially by activating a growth factor, TNF-alpha. Knowledge of this process and particularly its regulation is important for the treatment of pregnancy associated diseases that arise from improper implantation. These include infertility, placenta accreta, choriocarcinoma, miscarriage and pre-eclampsia. Furthermore, an understanding of the regulation of implantation will contribute to the treatment of other conditions associated with cell invasion such as cancer metastasis.Read moreRead less