Novel Interactions Between GnRH Receptor And E2F4 Transcription Factor.
Funder
National Health and Medical Research Council
Funding Amount
$462,750.00
Summary
The reproductive endocrine system is under the control of gonadotropin-releasing hormone (GnRH), signalling via its G-protein coupled receptor (GPCR) in the anterior pituitary gland. The GnRH receptor (GnRHR) is the drug target for the treatment of a range of endocrine-related disorders as well as hormone-dependent cancers. Sustained treatment with either GnRH agonists or antagonists can block gonadotropin secretion indirectly, via down-regulation of the pituitary receptor resulting in a reducti ....The reproductive endocrine system is under the control of gonadotropin-releasing hormone (GnRH), signalling via its G-protein coupled receptor (GPCR) in the anterior pituitary gland. The GnRH receptor (GnRHR) is the drug target for the treatment of a range of endocrine-related disorders as well as hormone-dependent cancers. Sustained treatment with either GnRH agonists or antagonists can block gonadotropin secretion indirectly, via down-regulation of the pituitary receptor resulting in a reduction of gonadotropin secretion and consequent decline in steroid production. As the majority of tumours treated with GnRH analogues are hormone-dependent, this starves the tumour of the steroid support required for growth. However, the concept of a direct anti-tumour effect of GnRH, independent of the pituitary-gonadal axis, is supported by the in vitro inhibition of both cell growth and DNA synthesis in a number of tumour cell lines. Despite the wide use of GnRH analogues, the molecular basis of the growth inhibitory effects resulting from the activation of this receptor is not fully understood. Unravelling the protein interactions underlying receptor-mediated signalling events will provide valuable information towards understanding of receptor function in vivo. We have identified a novel interaction involving the GnRHR and E2F4, a transcription factor involved in suppression of the transcription of genes involved in cell cycle progression. In addition, over 80% of E2F4 knockout mice are sterile. Owing to the role of the GnRHR in the reproductive pathway we are interested in determining whether the GnRHR-E2F4 interaction has an influence on the development of the hypothalamic-pituitary-gonadal axis, hence affecting reproductive capacity. The interaction identified and studied in this proposal has implications for the treatment of reproductive tumours, such as those of the breast and prostate, and understanding the development of the hypothalamic-pituitary-gonadal axis.Read moreRead less
Cysteine Rich Secretory Proteins (Crisp) Are Ion Channel Regulators With Essential Roles In Male Fertility
Funder
National Health and Medical Research Council
Funding Amount
$531,696.00
Summary
Male infertility affects 1 in 20 Australian men and for the majority of other men, contraception is an issue at some point in their lives. Despite this, relatively little is known about the processes of sperm production and fertilization. As such, there is an urgent need for futher research if we are to hope to develop diagnostics, targeted therapeutics and to take advantage of the growing awareness by pharmaceutical companies of the market for male gamete based contraceptives. The cysteine rich ....Male infertility affects 1 in 20 Australian men and for the majority of other men, contraception is an issue at some point in their lives. Despite this, relatively little is known about the processes of sperm production and fertilization. As such, there is an urgent need for futher research if we are to hope to develop diagnostics, targeted therapeutics and to take advantage of the growing awareness by pharmaceutical companies of the market for male gamete based contraceptives. The cysteine rich secretory proteins (Crisps) are a group of proteins which show a remarkable bias to the male reproductive tract. All four are incorporated into sperm. Recently published data from us indicates that they have the ability to regulated calcium flow in sperm and as such sperm activity. The aim of the current proposal is to explore the biological relevance of one domain of Crisp proteins using animal models, in vitro sperm tests and through an analysis of ion flux and phosphorylation status under conditions of altered Crisp-1 and -2 content. The data generated from this project will make a significant contribution to the development of novel male gamete based contraceptives for use by either men or women. In addition, through the attainment of a greater understanding of sperm development and function, we will be able to more precisely define types of infertility, thus allowing for the development of more targeted therapies. The development of Crisp agonists or antagonists may also be of value in the treatment of other cilia disorders including primary cilia dykinesia and cystic fibrosis.Read moreRead less
Regulation Of Growth Hormone Profile By Metabolic Balance: Neuronal, Neuroendocrinal And Molecular Mechanism
Funder
National Health and Medical Research Council
Funding Amount
$413,257.00
Summary
Obesity is associated with a reduction in growth hormone secretion. As growth hormone maintains muscle mass at the expense of fat this may further promote the obese condition. This project will determine the physiological role of ghrelin, a hormone that signals hunger, in maintaining growth hormone secretion under normal, fasting and obese conditions. Clarification of the role of ghrelin in regulating growth hormone secretion may aid in the development of pharmacological agents to assist and mai ....Obesity is associated with a reduction in growth hormone secretion. As growth hormone maintains muscle mass at the expense of fat this may further promote the obese condition. This project will determine the physiological role of ghrelin, a hormone that signals hunger, in maintaining growth hormone secretion under normal, fasting and obese conditions. Clarification of the role of ghrelin in regulating growth hormone secretion may aid in the development of pharmacological agents to assist and maintain weight loss.Read moreRead less
Implantation of an embryo into the uterus & development of a functional placenta are critical to initiate & continue a pregnancy. Implantation failure causes infertility and is a major bottle-neck in IVF. Placental insufficiency leads to pregnancy loss, under-developed fetuses & a life-threatening pregnancy-specific disease preeclampsia. This application will investigate how a woman’s uterus works for implantation and placental development, how to increase IVF success and diagnose & potentially ....Implantation of an embryo into the uterus & development of a functional placenta are critical to initiate & continue a pregnancy. Implantation failure causes infertility and is a major bottle-neck in IVF. Placental insufficiency leads to pregnancy loss, under-developed fetuses & a life-threatening pregnancy-specific disease preeclampsia. This application will investigate how a woman’s uterus works for implantation and placental development, how to increase IVF success and diagnose & potentially treat preeclampsia.Read moreRead less
Pain changes movement. Although undisputed, there is a surprising lack of agreement regarding the underlying mechanisms. This project involves an innovative mix of neurophysiological methods to investigate the drive to muscle cells from the nervous system and changes in the mechanics of contraction. These studies will resolve the perplexing problem of how pain changes our ability to activate muscle. Clear understanding of the underlying mechanisms can guide rehabilitation.
Targeted Disruption Of Lipoxygenase Enzymes To Prevent Oxidative Stress-mediated Pathologies In The Male Germline
Funder
National Health and Medical Research Council
Funding Amount
$408,768.00
Summary
An estimated 80 million individuals suffer from infertility globally with at least 50% of these cases due to defects in sperm function. Unfortunately, due to a severe lack of knowledge surrounding sperm biology and dysfunction, no successful curative or preventative measures have been established. My project will study why sperm cells die and investigate new ways to limit cellular stress so we can develop new therapeutic strategies to mitigate the growing problems in male reproductive health.
Metabolic And Molecular Basis Of Embryo Signalling
Funder
National Health and Medical Research Council
Funding Amount
$409,836.00
Summary
Cells in the body are powered by mitochondria that essentially generate the energy required for development. This grant will determine how the environment affects the mitochondria in the developing embryo and determine the impacts to the embryo and pregnancy if a mitochondria is partially shut down.
It is clear that the health and disease burden of offspring can be programmed by events before birth. This project will answer questions as to how this programming occurs. My focus is to understand how the environment affects the oocyte, sperm and embryo and how this impacts on the offspring. We will specifically study the effects of obesity and nutritional status of the parents but also the in vitro environment with a view to improving IVF outcomes.
Activin And Its Binding Protein, Follistatin Regulate Functions Of The Epididymis And Vas Deferens
Funder
National Health and Medical Research Council
Funding Amount
$612,736.00
Summary
Male reproductive disease is a serious health issue for many men and their partners. Worldwide, malformations of the male reproductive organs are increasing, infections and chronic inflammation of the genitourinary tract beset sexually active men and aging men, and infertility afflicts one in seven couples desiring children. The causes underlying these conditions are not well-understood. These studies are intended to identify new approaches for preventing and treating these conditions.