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

Ca2 信号传导在人类精子行为的调节和治疗操作中的作用

• 批准号: MR/M012492/1
• 负责人: Stephen Publicover
• 金额: $ 63.09万
• 依托单位: University of Birmingham
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FM012492%2F1
• 关键词: Ca2+; signalling; regulation; therapeutic; manipulation

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.

精子的游泳能力对人类受精至关重要。精子不仅必须是能动的，它们还必须能够执行具有不同功能的不同游泳“风格”，并根据需要使用它们。当精子从阴道迁移到输卵管，在那里它将使卵子受精，它必须通过非常不同类型的液体和凝胶，必须通过复杂的三维环境，然后必须穿透围绕卵子的两层“外套”，首先是一层厚厚的小细胞嵌入果冻（卵丘细胞），在这层里面是一层坚韧的蛋白质外壳（透明壳）。为了在所有这些不同的旅程阶段取得成功，精子必须在每个阶段正确地选择各种游泳方式，甚至将它们结合起来，在两种方式之间交替使用。这个复杂的过程是由女性生殖道提供的线索精心策划的，但也取决于精子内部的事件。这些线索导致精子细胞内钙离子（Ca 2+）浓度的变化，这反过来又作为选择游泳类型的信号。我们最初的实验表明，精子至少有两种不同的方法可以控制细胞内Ca 2+的浓度，当我们选择性地用药物刺激细胞以激活这两种Ca 2+“途径”中的一种时，根据我们开启的方法，我们可以使精子以非常不同的方式游泳。在这项研究中，我们将测量精子的Ca 2 +浓度和精子游泳风格时，他们提供的线索，他们会满足，因为他们通过女性管道旅行，并满足卵子。我们将研究打开的Ca 2+“信号”的类型（使用哪种Ca 2+途径），产生的信号的特征以及女性管道提供的不同线索如何选择不同类型的Ca 2+信号，从而如何控制精子的游泳方式。我们从这些实验中获得的理解将用于研究生育力低下男性的精子。我们将研究这些过程是如何在精子不能调节其活力和游泳方式的男性中出错的-这是男性不育的重要原因。最后，我们将利用这些关于如何控制精子游泳的信息来测试药物，这些药物可能用于“激活”通常无法正常游泳的精子，因此无法到达卵子和/或当它们到达那里时无法使其受精。对于这个问题严重影响生育能力的男性来说，以这种方式纠正或绕过这个问题将提供一种简单、低成本的治疗途径，而不需要使用高度侵入性、潜在创伤性和非常昂贵的体外辅助生殖技术。

项目成果

Complex CatSper-dependent and independent [Ca2+]i signalling in human spermatozoa induced by follicular fluid.

• DOI: 10.1093/humrep/dex269
• 发表时间: 2017-10-01
• 期刊: Human reproduction (Oxford, England)
• 作者: Brown SG;Costello S;Kelly MC;Ramalingam M;Drew E;Publicover SJ;Barratt CLR;Da Silva SM
• 通讯作者: Da Silva SM

Depolarization of sperm membrane potential is a common feature of men with subfertility and is associated with low fertilization rate at IVF.

• DOI: 10.1093/humrep/dew056
• 发表时间: 2016-06
• 期刊: Human reproduction (Oxford, England)
• 作者: Brown SG;Publicover SJ;Mansell SA;Lishko PV;Williams HL;Ramalingam M;Wilson SM;Barratt CL;Sutton KA;Da Silva SM
• 通讯作者: Da Silva SM

Specific loss of CatSper function is sufficient to compromise fertilizing capacity of human spermatozoa.

• DOI: 10.1093/humrep/dev243
• 发表时间: 2015-12
• 期刊: Human reproduction (Oxford, England)
• 作者: Williams HL;Mansell S;Alasmari W;Brown SG;Wilson SM;Sutton KA;Miller MR;Lishko PV;Barratt CL;Publicover SJ;Martins da Silva S
• 通讯作者: Martins da Silva S

Homozygous in-frame deletion in CATSPERE in a man producing spermatozoa with loss of CatSper function and compromised fertilizing capacity.

• DOI: 10.1093/humrep/dey278
• 发表时间: 2018-10-01
• 期刊: Human reproduction (Oxford, England)
• 作者: Brown SG;Miller MR;Lishko PV;Lester DH;Publicover SJ;Barratt CLR;Martins Da Silva S
• 通讯作者: Martins Da Silva S

Single-cell analysis of [Ca2+]i signalling in sub-fertile men: characteristics and relation to fertilization outcome.

• DOI: 10.1093/humrep/dey096
• 发表时间: 2018-06-01
• 期刊: Human reproduction (Oxford, England)
• 作者: Kelly MC;Brown SG;Costello SM;Ramalingam M;Drew E;Publicover SJ;Barratt CLR;Martins Da Silva S
• 通讯作者: Martins Da Silva S