Ca2+ signalling in regulation and therapeutic manipulation of human sperm behaviour

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Then ability of sperm to swim is vital for human fertilization. Not only must sperm be motile, they must also be able to perform different swimming 'styles' with different functions and employ them as needed. As the sperm migrates form the vagina to the oviduct, where it will fertilise an egg, it must progress through very different types of fluid and gel, must navigate through complex, 3-dimensional environments and must then penetrate two 'coats' that surround the egg, first a thick layer of small cells embedded in jelly (the cumulus cells) and inside this a tough, protein shell (the zona pellucida). To succeed at all these different stages of its journey the sperm must, at each stage, select correctly from its various swimming styles or even use them in combination, alternating between two. This sophisticated process is orchestrated by cues provided by the female tract but also depends on events inside the sperm. The cues cause a change in the concentration of calcium ions (Ca2+) inside the sperm cell, which in turn acts a as a signal to select the type of swimming to use. Our initial experiments have shown us that there are at least two different methods by which the sperm can control the concentration of Ca2+ inside the cell and that when we stimulate the cells with drugs selectively to activate one or other of these two Ca2+ 'pathways', we can cause the sperm to swim in very different styles according to which method we turn on. In this study we will measure sperm Ca2+ concentration and sperm swimming style when they are provided with cues that they would meet as they travel through the female tract and meet the egg. We will investigate the types of Ca2+ 'signal' that are turned on (which Ca2+ pathway is used), the characteristics of the signal produced and how the different cues provided by the female tract can select different types of Ca2+ signal and thus how they are able to control what kind of swimming the sperm does. The understanding that we gain from these experiments will be used to study sperm from subfertile men. We will investigate how these processes go wrong in men whose sperm cannot regulate their motility and swimming style - an important cause of male infertility. Finally, we will use this information on how sperm swimming is controlled to test drugs that will potentially be used to 'activate' sperm that normally fail to swim properly and therefore cannot reach the egg and/or cannot fertilise it when they get there. For men where this problem significantly affects their fertility, correcting or bypassing the problem in this way will provide a route for simple, low cost treatment without needing to use the highly invasive, potentially traumatic and very expensive techniques of in vitro assisted reproduction.