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| Uterine Biology |
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Research Trial: |
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1. Mining the human endometrial proteome: newly discovered proteins and their relevance to infertility Supervisors : Professor Lois Salamonsen and Dr Jemma Evans (honours and PhD projects) Contact: lois.salamonsen@princehenrys.org Implantation of the embryo into the womb is an essential step for pregnancy. Successful implantation requires two components, a viable embryo and a receptive endometrium. Our work is focusing on how the endometrium becomes receptive for implantation and in particular on the molecular signature within the tissue, that defines receptivity. To this end, we have undertaken a discovery program using a state-of-the-art proteomics platform. This has identified a number of previously unknown proteins and pathways that are highly regulated in the endometrium at the time of uterine receptivity. The project/s will examine such proteins: their expression patterns, regulation and function in the endometrium using a range of relevant in vitro (human) and in vivo (mouse) models and where appropriate, will also determine whether the protein/s are dysregulated in women with infertility.
2. PC6 as a potential target for developing dual-role female contraception by simultaneously blocking embryo implantation and HIV infection Supervisor: Dr Guiying Nie Proprotein convertases (PCs) are a family of “master switch” serine proteases essential for activating numerous protein precursors of critical importance. We have identified that one member of this family, PC6, is critical for making the uterus receptive for embryo implantation. Knockdown of PC6 in the uterus completely inhibits embryo implantation. Clinically this is a very significant finding because PCs are also involved in HIV infection and their inhibition is suggested to be an effective approach to reduce HIV infection. We propose that PC6 is a novel target to develop female contraception which could also protect women from HIV infection. This project will investigate the molecular mechanism of PC6 action during embryo implantation in mice in vivo and in cell models relevant to human implantation, and explore various ways of inhibiting PC6 to prevent embryo implantation and HIV infection. The findings will be essential towards developing clinically important strategies for PC6 inhibition towards the development of dual-role contraception. Techniques include in vitro cell culture models, manipulations of mice in vivo, cloning and transient transfection, proteomics, Western blotting and real time RT- PCR.
3. Role of PC6 regulated proteins in uterine fertility and infertility Supervisor: Dr. Guiying Nie Proprotein convertases (PCs) are a family of “master switch” serine proteases essential for activating numerous protein precursors of critical importance. In particular, we have shown that PC6 is essential in the mouse uterus for successful implantation of an embryo. By proteomic techniques, we have identified a group of proteins which are tightly regulated by PC6 in the human endometrium. These PC6 substrates have never been characterised in the human endometrium and their contribution to normal and abnormal endometrial function is unknown. Using a variety of techniques including western blot analysis, immunohistochemistry, cell culture and real-time PCR, this project will determine the expression and localisation of these proteins in normal endometrium and determine their function in uterine fertility and infertility.
4. Role of a novel gene in placental development, function and pregnancy disorders Supervisors: Dr Guiying Nie We have recently discovered and cloned a novel gene, HtrA3, in the mouse and human, and identified that it is a previously unrecognized factor important for placental development and function. The current projects will investigate the molecular mechanisms of HtrA3 action during placental development in mice and human, and to determine the contribution of HtrA3 dys-regulation in pregnancy disorders such as pre-eclampsia. In addition, the long-term consequences of sub-optimal foetal growth in utero on the health of the resultant adults as they age (e.g., increased risks of developing obesity and diabetes) will be investigated. Techniques include using genetically modified mice, in vitro cell models with human endometrial and placental cells, siRNA application and proteomics.
5. The interface between aging and cancer: the role of a newly identified gene Supervisors: Dr Guiying Nie and Professor Lois Salamonsen It is increasingly recognized that cancer occurs predominantly in older persons. More than 60% of new cancers and more than 70% of cancer deaths occur in people over the age of 65 years. Although it is well accepted that aging and cancer are intertwined, our knowledge about the relationship between aging and cancer at the biological levels is very limited; studies that address this knowledge gap are urgently needed. We have recently cloned a new gene called HtrA3 which we first identified in the placenta. We have knocked out this gene in the mouse and find that mice lacking HtrA3 spontaneously develop a number of cancers as they age. These mice now provide us a unique animal model and an exciting opportunity to address the biological interrelationship between aging and cancer. This project will identify the biological reasons why older mice lacking HtrA3 are prone to develop cancer, and to identify the roles of HtrA3 in cancer development and progression with aging in the human population.
6. Infertility: exploring the function and mechanisms of critical mediators Supervisors: Dr Eva Dimitriadis and Professor Lois Salamonsen Failure of embryo implantation leads to infertility. O f the 1 in 10 couples having problems conceiving, 25% have unexplained infertility. Thirty percent of all pregnancies end in spontaneous abortion. Infertility and early pregnancy loss is a significant health burden and currently there is no way of diagnosing primary infertility. We have identified molecules that are critical for the very initial stages of implantation. This project aims to identify precisely how these molecules act to regulate the very early stages of implantation, i.e. the adhesion of the embryo to the endometrium. The project will use our new world class proteomics facility, primary human cell culture systems, molecular biology, histopathology, biochemical and likely animal models. Part of this study will be performed in collaboration with colleagues internationally and nationally. The results form this study may lead to much needed endometrial markers of infertility.
7. Endometrial – placental interactions: implications in infertility and adverse pregnancy outcomes Supervisors: Dr Eva Dimitriadis and Professor Lois Salamonsen The successful implantation of the human embryo into a receptive endometrium leads to the formation of a functional placenta, a successful pregnancy and hence a normal baby. Inadequate implantation leads to abnormal placentation. If the placenta does not form adequately, this can result in early miscarriage, pre-eclampsia and intrauterine growth restriction. Preeclampsia can result in intrauterine growth retardation, prematurity and even maternal death. Thirty percent of all pregnancies end in spontaneous miscarriage. Currently there is no way of diagnosing which women will miscarry or develop pre-eclampsia. There are currently no therapeutics available for these diseases. Our lab is trying to unravel the roles of novel uterine and placental derived factors that are critical for the early placental endometrial factors that are critical for establishment of the placenta The project will use our new world class proteomics facility, primary human cell culture systems, molecular biology, histopathology, biochemical and animal models. The new knowledge obtained from these studies may lead to much-needed diagnostic and therapeutic tools for major diseases associated with pregnancy for which there are currently no treatment options.
8. Development of a novel non-hormonal dual role contraceptive (also prevents sexually transmitted diseases including HIV) Supervisors: Dr Eva Dimitriadis and Prof Lois Salamonsen New contraceptive options are urgently needed for women world-wide (Glasier and Gulmezoglu, 2006). More than 700,000 maternal deaths, most in the developing world and related to causes associated with unintended pregnancies, occurred between 1995 and 2000; more than 400,000 of these deaths resulted from unsafe abortions (Glasier and Gulmezoglu, 2006). Acquired immune deficiency syndrome (AIDS) appears to thrive in the presence of overpopulation and other sexually transmitted diseases (STDs). There is a recognised world-wide need to develop novel targeted methods of contraception. We are investigating the contraceptive potential and action of two novel cytokine inhibitors in collaboration with industry and non-industry partners. This work is funded by the only non-profit agency worldwide to fund contraceptive research (CONRAD/CICCR, USA). This project utilizes animal models, human cell culture models, histopathology, biochemical and molecular approaches. This project will provide valuable information that may contribute to the development of novel dual contraceptive/anti-STD agents for women. |
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