Male Infertility And Defective Sperm-oocyte Interaction
Funder
National Health and Medical Research Council
Funding Amount
$244,614.00
Summary
Infertility affects 15% of people and although not usually ill, they are extremely distressed by the condition. In vitro fertilisation (IVF) with normal sperm and intracytoplasmic sperm injection for sperm defects, can assist such patients have a family, but these treatments are expensive and not always successful. The causes of male infertility are largely unknown, diagnostic methods are crude and there is usually no treatment to promote natural conception. Conventional semen analysis provides ....Infertility affects 15% of people and although not usually ill, they are extremely distressed by the condition. In vitro fertilisation (IVF) with normal sperm and intracytoplasmic sperm injection for sperm defects, can assist such patients have a family, but these treatments are expensive and not always successful. The causes of male infertility are largely unknown, diagnostic methods are crude and there is usually no treatment to promote natural conception. Conventional semen analysis provides limited information on fertilising ability. Our work over 15 years has shown that many patients go undiagnosed, particularly those with defects impairing fertilisation. During human fertilisation, sperm bind to the zona pellucida, a coat around the egg, via the membrane over a cap like structure on the sperm head called the acrosome. Binding of a sperm triggers the acrosome reaction, the process by which the membranes covering the acrosome fuse and the acrosomal contents are released. The sperm then penetrates the zona pellucida, binds to the membrane of the egg and is taken into the cytoplasm. We have developed tests to assess sperm binding to the zona pellucida and the acrosome reaction using eggs that failed to fertilise during clinical IVF. These tests show defects of sperm binding to the zona pellucida and the zona pellucida induced acrosome reaction are present in over 25% of patients without other obvious causes for their infertility. The men are severely infertile but have normal sperm by conventional tests. In this project we will determine if there are changes in membrane proteins in sperm which do not bind to the zona pellucida or undergo the acrosome reaction. We will categorise patients on the responses of their sperm to activation of key enzymes and other regulatory molecules involved in the fertilisation process. This will allow us to select subjects for further examination of protein abnormalities and genetic causes of the conditions.Read moreRead less
Approximately 1 in 25 men in the western world are infertile, and while environmental and genetic factors are recognized to contribute to disease, there is currently a poor understanding of the basic mechanisms regulating male fertility. Our long term goal is to identify and study key molecules involved in sperm production. Understanding the role of these molecules will provide insight into the causes of male infertility. Ultimately, these studies will assist to develop new treatments for male r ....Approximately 1 in 25 men in the western world are infertile, and while environmental and genetic factors are recognized to contribute to disease, there is currently a poor understanding of the basic mechanisms regulating male fertility. Our long term goal is to identify and study key molecules involved in sperm production. Understanding the role of these molecules will provide insight into the causes of male infertility. Ultimately, these studies will assist to develop new treatments for male reproductive disorders. Conversely, there is a huge need for additional male based contraceptives. Increased understanding of male fertility and identification of proteins exclusively involved in sperm production provides the opportunity to develop new contraceptive treatments.Read moreRead less
Head Development: Genetic Determinants And Tissue Potency
Funder
National Health and Medical Research Council
Funding Amount
$947,116.00
Summary
Congenital malformations involving major defects of brain (anencephalus and related anomalies) and facial structures (ear, face and neck) are encountered in 3.4 and 1.4 per 10000 births respectively (Congenital Malformations Australia 1981-1996, National Perinatal Statistics Unit) and they constitute a substantial clinical burden. It is believed that these major structural defects usually result from abnormal development in the first trimester, which coincides with the time frame for the formati ....Congenital malformations involving major defects of brain (anencephalus and related anomalies) and facial structures (ear, face and neck) are encountered in 3.4 and 1.4 per 10000 births respectively (Congenital Malformations Australia 1981-1996, National Perinatal Statistics Unit) and they constitute a substantial clinical burden. It is believed that these major structural defects usually result from abnormal development in the first trimester, which coincides with the time frame for the formation of the basic components of the embryonic head in the mouse. Knowledge of the formation of the head in the mouse model is therefore relevant to the understanding of related developmental processes in early human development. This project which involves the application of sophisticated embryological and molecular analyses on mouse embryos generated by transgenesis and genetic manipulation provides a detailed studies of craniofacial morphogenesis in a mammalian model for early human development. The micro-manipulation procedures, embryo culture, fluorescence microscopy and the in situ hybridization are routinely performed in our laboratory, and most of the mouse lines are well established in my laboratory. Experiments proposed for this project that focus on the embryological and molecular analysis of normal and mutant embryos should discover new information on the cellular and molecular mechanisms that regulate head development. The knowledge will also offer insight into the pathogenesis of similar craniofacial malformations in other mutant embryos.Read moreRead less
It is now well established that there are genetic factors contributing to risk of depression but it is far from clear what these are and how they interact with environmental risk factors such as stressful life events (SLE) and poor social support (SS). A recent, highly cited paper has claimed that those carrying a particular genotype at the sertonin transporter gene are much more badly affected by stressful life events than other genotypes, and that this puts these people at much higher risk of ....It is now well established that there are genetic factors contributing to risk of depression but it is far from clear what these are and how they interact with environmental risk factors such as stressful life events (SLE) and poor social support (SS). A recent, highly cited paper has claimed that those carrying a particular genotype at the sertonin transporter gene are much more badly affected by stressful life events than other genotypes, and that this puts these people at much higher risk of depression. If true, this could have important practical implications for preventative mental health, in identifying those at greatest risk if depression and counselling them to avoid stressful situations. However, success in replicating this finding has been mixed, and this is possibly because another important risk factor, social support, has not been taken into account. We have DNA samples from over 5000 twins who have been assessed for depression and risk factors including SLE and SS. This will give us unprecedented power to estimate the importance of the genotype x environment interaction. We shall also type other genes that have been implicated in depression and check for interactions with life events and social support. Our results will inform preventative strategies in mental health practice.Read moreRead less