Decoding microtubule remodelling in sperm production. All eukaryotic cells possess a dynamic microtubule (MT) cytoskeleton, which requires constant remodelling to satisfy its many essential cellular roles. Emerging data suggests modifications to the MT surface (the tubulin code) may act as instructional signposts for remodelling. This project aims to define a fundamental component of the tubulin code, glutamylation, and define how this directs MT severing. It also aims to define the cellular fun ....Decoding microtubule remodelling in sperm production. All eukaryotic cells possess a dynamic microtubule (MT) cytoskeleton, which requires constant remodelling to satisfy its many essential cellular roles. Emerging data suggests modifications to the MT surface (the tubulin code) may act as instructional signposts for remodelling. This project aims to define a fundamental component of the tubulin code, glutamylation, and define how this directs MT severing. It also aims to define the cellular functions of MT-severing enzyme FIGNL1 and key MT glutamylation enzymes (CCP1, CCP5 and TTLL1). Insights will be generated using sperm production as a model system and will thus inform the mechanisms by which fertile sperm are built, in addition to being relevant to cell biology across eukaryotic species. Read moreRead less
Disorders of sexual development are among the most common form of birth defects in humans (1 in 4,000 births) because failure of the gonads to develop does not affect the viability of the individual. Such disorders can have profound psychological and medical consequences upon the individual, family, and society. Some intersexual conditions are the result of inappropriate exposure to hormones during fetal life, and others are due to spontaneous or inherited gene mutation. About 5-10% of ovarian c ....Disorders of sexual development are among the most common form of birth defects in humans (1 in 4,000 births) because failure of the gonads to develop does not affect the viability of the individual. Such disorders can have profound psychological and medical consequences upon the individual, family, and society. Some intersexual conditions are the result of inappropriate exposure to hormones during fetal life, and others are due to spontaneous or inherited gene mutation. About 5-10% of ovarian cancer cases, that affect 1 in 8000 Australian women, are due to the inheritance of a faulty gene. An understanding of the way gene expression and hence tissue differentiation is altered after sex reversal will inform us about the causes and consequences of normal and abnormal sexual development, gonadal malignancies and infertility. The gonad is unusual in that two completely different organs can arise from an essentially identical primordium, so that errors in development lead to intersexual phenotypes. We will use our new experimental animal model to clarify these processes.Read moreRead less
Male germ line transgenesis and siRNA technology for manipulating genes in domestic species. Professor Shemesh has successfully developed male germ line transgenesis in species such as bovine and chicken. This technology allows genes to be manipulated via sperm in a wide range of animals besides mice, avoiding the need for a female in vitro fertilization regimen. He is curently applying interference RNA (siRNA) transgenically to manipulate genes in vivo. Together these two technologies offer imm ....Male germ line transgenesis and siRNA technology for manipulating genes in domestic species. Professor Shemesh has successfully developed male germ line transgenesis in species such as bovine and chicken. This technology allows genes to be manipulated via sperm in a wide range of animals besides mice, avoiding the need for a female in vitro fertilization regimen. He is curently applying interference RNA (siRNA) transgenically to manipulate genes in vivo. Together these two technologies offer immense possibilities to manipulate a wide range of species for economic, biotechnological or medical research purposes. Professor Shemesh wishes to come to Adelaide to establish these technologies there as parts of ongoing research projects, related to the physiology of the ovarian hormone relaxin in aging research.Read moreRead less
Roles Of TGFbeta Receptor TGFBR3 (Betaglycan) In Testis Development
Funder
National Health and Medical Research Council
Funding Amount
$332,660.00
Summary
Diseases of the reproductive tract are major health issues. At lease 1 in 100 live births display some sort of gonadal defects. Later in adulthood, one in six couples are affected by infertility, and cancers of the reproductive tract which result in a significant number of deaths each year. This project focuses on understanding the role of the transformation growth factor beta receptor3 (Tgfbr3) in the embryonic and neonatal testis and its impact on adult male reproductive capacities and health.
I am a reproductive biologist, studying how the environment, both in vivo and in vitro, interacts with oocytes and early embryos in determining both their short and long-term development, with specific interests in application to clinical infertility treatment.
A Novel Procedure For Efficacious Gonadotrophin-free Infertility Treatment
Funder
National Health and Medical Research Council
Funding Amount
$436,328.00
Summary
Infertility is common and is associated with health risks and is expensive. Using laboratory animals, we have developed a unique procedure, which has comparable success rates to IVF but crucially, it eliminates the need for ovarian hormone therapy used in IVF. A clinical trial using this method has started in Brussels and in this project we will examine cells from that trial and from animals to investigate the underlying mechanisms to enable safe and rapid clinical implementation.
GM-CSF Regulation Of Preimplantation Embryo Development
Funder
National Health and Medical Research Council
Funding Amount
$481,320.00
Summary
Treatment of infertility using IVF technology has been enormously successful. However, there are major concerns regarding the high incidence of multiple pregnancies (caused by the transfer of more than one embryo) and the potential adverse health outcome of adults conceived from this technology. Multiple pregnancies place both mother and infant at enormous risks, with increased obstetrics care, prematurity, increased neonatal care and neurological disorders such as cerebral palsy. This can be ov ....Treatment of infertility using IVF technology has been enormously successful. However, there are major concerns regarding the high incidence of multiple pregnancies (caused by the transfer of more than one embryo) and the potential adverse health outcome of adults conceived from this technology. Multiple pregnancies place both mother and infant at enormous risks, with increased obstetrics care, prematurity, increased neonatal care and neurological disorders such as cerebral palsy. This can be overcome simply by the transfer of a single embryo. However, patient and clinical expectations are that single embryo transfer should be achieved with little to no reduction in pregnancy rate, and currently this is not possible because our methods for culturing embryos are inadequate. Studies in animals suggest that laboratory growth of mammalian embryos can lead to small-for-gestational age babies (even when the effect of multiple births is taken into consideration). This backed by recent studies which agree that babies born from IVF are smaller than expected. This might lead to health problems in later life, as smallness at birth is associated with higher risks of cardiovascular disease and diabetes, especially as age progresses beyond 40 years. However, the oldest IVF child is currently 23 years of age. Previously we have shown that a protein growth factor, called granulocyte-macrophage colony-stimulating factor (GM-CSF), found normally in the reproductive tract, has dramatic beneficial effects on human and mouse embryos grown in the laboratory. Furthermore, we have shown in mice that embryo exposure to GM-CSF alleviates the detrimental side effects of in vitro culture on foetal growth and body structure after birth. Our research is now focussed on understanding why this protein is beneficial to embryo growth and to test if we can increase pregnancy rates and produce normal healthy infants from the transfer of single embryos treated with GM-CSF.Read moreRead less
Sperm ciliary gating and midpiece formation – a novel player and process. We have identified CCDC112 an essential player in mammalian sperm tail development and male fertility. This project aims to define the role of CCDC112 in 1) the formation of the core to the sperm tail, the axoneme, and 2) the packaging of mitochondria into the midpiece. Within this Discovery Project we will define the mechanism(s) of CCDC112 functions and the consequences of its dysfunction. Insights from this grant will b ....Sperm ciliary gating and midpiece formation – a novel player and process. We have identified CCDC112 an essential player in mammalian sperm tail development and male fertility. This project aims to define the role of CCDC112 in 1) the formation of the core to the sperm tail, the axoneme, and 2) the packaging of mitochondria into the midpiece. Within this Discovery Project we will define the mechanism(s) of CCDC112 functions and the consequences of its dysfunction. Insights from this grant will be of significance to fertility across mammals and may ultimately benefit the selection of highly fertile males within the agricultural sector.Read moreRead less
Testis To Ovary: Hormonal Control Of Differentiation
Funder
National Health and Medical Research Council
Funding Amount
$803,379.00
Summary
We know very little of the genes that control development of the ovary in female fetuses; most study has focused on the formation of the testis in males. We will use a novel experimental model, a marsupial, where by hormonal treatment of developing males we can switch off testis formation and activate the ovarian pathway. These studies will potentially shed new light on the causes of reproductive diseases including ovarian cancer, as well as clarifying the basic biological processes that guide f ....We know very little of the genes that control development of the ovary in female fetuses; most study has focused on the formation of the testis in males. We will use a novel experimental model, a marsupial, where by hormonal treatment of developing males we can switch off testis formation and activate the ovarian pathway. These studies will potentially shed new light on the causes of reproductive diseases including ovarian cancer, as well as clarifying the basic biological processes that guide formation of the ovary.Read moreRead less