Research in the areas of embryology and infertility focuses around the properties of the gametes (egg and sperm), their interaction during fertilisation and the development of the early embryo. Our goals are to understand the causes of infertility and the mechanisms controlling the behaviour of early embryo cells (and their in vitro equivalents, embryonic stem cells).
People Professor Christopher Barratt - Understanding the regulation of human sperm function and the development of novel treatments for male infertility (see below).
Dr Marios Stavridis - Embryonic stem cell biology (see below).
Professor Aleksandar Jovanovic - Investigating ion channels in human oocytes. In this project we are trying to examine specific channels in human oocytes (potassium ATP channels) which may be involved in regulating the stress levels in the eggs in vitro (see below). Professor Jovanovic is in the Centre for Cardiovascular & Lung Biology.
We have strong links with the Assisted Conception Unit and collaborate on various translational research projects.
We are also part of the Dundee Stem Cell Initiative and have links with other researchers in it.
Male sub-fertility is a very significant global problem and most worryingly evidence suggests its prevalence is increasing. Already it affects 1 in 15 men and is primarily manifested as impaired sperm function. In view of the scale of the problem, remarkably few drug treatments to enhance sperm function have been investigated and none has proven to be effective in controlled trials. A fundamental prerequisite to developing drug therapy is a detailed understanding of the functioning of the normal and dysfunctional cell. Our rudimentary knowledge of human sperm function remains a severe obstacle to the development of effective drugs (Barratt et al, 2009).
In this project we will be studying function of the cell in particular how the cell responds to chemicals produced by the female tract which activate the sperm. The movement of sperm through the female reproductive tract is a controlled process and not the straight forward race to the egg that many imagine. During most of the journey the female reproductive tract holds back the sperm from being ready to fertilize the egg in order to help preserve their viability. However, as the sperm approach the egg they have to be activated before they can fertilize. We are interested in the roles of two messengers, progesterone and nitric oxide, secreted by the cumulus cells that surround the egg in this whole process. These messengers act together to regulate the function of the cells. We want to find out the pathways responsible for activating the sperm. Shortly before the sperm interacts with the egg it adopts an erratic swimming mode known as ‘hyperactivated motility’. We would like to further understand this process of hyperactivation by determining the signal that induces hyperactivation and the manner by which the signal is transmitted.
We are also interested in proteins that may be related to sperm motility. Of interest are phosphodiesterase enzymes, which decrease the concentrations of a messenger molecule called cAMP. We believe that increasing the concentration of cAMP by inhibiting phosphodiesterases may enhance sperm motility. Inhibition of another enzyme, phosphatidylinositol 3-kinase, is believed to increase sperm motility. However, new research suggests that other enzymes may be responsible for enhancing sperm motility and we would like to identify those as yet unidentified proteins.
The aim of our research is to further understand the mechanisms whereby sperm are able to fertilize eggs. We have evidence to show that the sperm is activated by at least two interrelated mechanisms. One is generation of chemical messages in the cell and the other is changes in protein composition. The protein composition changes are: protein phosphorylation and, protein S-nitrosylation. This latter is a recently discovered chemical modification involved in the control of protein function that has not previously been investigated in sperm. We are interested in examining these pathways and determining if they are abnormal in some men with sub fertility. In addition we would like to test enzyme inhibitors to see if we can enhance sperm motility and hope that in the future we may be able to develop drugs which may be able to improve IVF success.
Embryonic stem cells have the ability to differentiate into all cell types found in the body. This ability has led to the expectation that embryonic stem cells will one day be used to treat many diseases such as diabetes, Parkinson’s etc. Before such therapeutic applications are realised, we must understand more about how to generate specific cell types from embryonic stem cells efficiently and safely in the laboratory. Our work focuses on understanding how embryonic stem cells interpret signals from their environment to control their behaviour (i.e. to start differentiating or not). This will ultimately lead to a better understanding of cell behaviour and may lead to better ways of manipulating it to generate the desired cell types.
Growth factor control of differentiationWork from us and others has demonstrated that a particular type of signal (from a protein family called fibroblast growth factor or Fgf) is required for mouse embryonic stem cells to begin their differentiation. We have also found that Fgf signals this by activating a protein called Erk (Stavridis et al, 2007). We are now studying how Erk is involved in the differentiation in mouse embryonic stem cells using a variety of cell culture and molecular biology techniques. We are also interested in understanding how human embryonic stem cells begin their differentiation and whether Erk is also involved in this process.
Infertility is a very significant global problem. However, our yet incomplete knowledge of human egg function remains a severe obstacle to the development of more efficient strategies against infertility.
In this project we will be studying the properties of eggs. More specifically, we plan to identify ion channels (protein structures that are crucial for movement of ions and cell interaction with the external environment) cell present in the egg membrane and how their behaviour affects egg function. In turn, this knowledge will help establishing novel, more efficient, therapies for infertility.
The aim of our research is to improve our understanding of the structure, regulation and function of ion channels present in the membrane of human eggs.
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