Spectroscopic Probes of Energy Regulation & Metabolism (SPERM): Using High Resolution MR spectroscopy to identify biomarkers of male fertility

大约20%的年轻男性精液质量差，50%的试管受精夫妇的男性精子有问题。虽然问题通常是因为男性精子数量少，但有时是因为他的精子游得不好。在这种情况下，精子可以注射到他伴侣的卵子中来帮助受精（这个过程被称为细胞质内精子注射或ICSI）。但这增加了不孕症治疗的费用，而且并不总是由NHS资助。目前还没有有效的治疗方法来改善精子的活力，但是能够给精子“提振”可能会避免像ICSI这样的高科技手术，而不是技术含量较低的手术，或者如果治疗非常成功，可以完全避免辅助受孕的需要。不幸的是，我们对精子产生能量的方式知之甚少，这些能量是它们的尾巴拍打和推动它们前进所必需的。他们有很多方法可以做到这一点，他们可以燃烧一系列不同的“燃料”。因此，在这个项目中，我们建议使用放射科医生开发的一些技术来检查癌细胞使用的能量途径，以开发新的化疗方法。这些技术依赖于检测原子置于磁场中时的分子特征，与医生扫描病人以观察其内部（核磁共振成像）的技术非常相似。我们已经开发出一种方法来准备精子，并将它们放入扫描仪中，试点数据表明，我们可以看到参与精子能量产生的关键分子。此外，我们还向精子中添加了一些标记为“燃料”的东西，以观察它们如何使用它们。这表明我们的技术是有效的，现在我们计划对不同男性的精子进行更全面的分析。我们将从不同生育能力的男性中获取精液，并准备在不同条件下扫描他们的精子。我们将研究是否能在精子游得好和游得差的男性之间发现用于制造和提供精子能量的分子的差异。此外，我们还将尝试在同一个人身上分离出游泳能力好的精子和游泳能力差的精子，看看我们是否能发现差异。如果我们能做到，那么这可能会导致两项临床进展。首先，它可以让我们开发出一种更好的精子活力诊断测试，比目前的方法更容易、更便宜。目前，为了诊断与精子活力低下有关的男性不育症，科学家必须使用光学显微镜观察精子的活力。这是劳动密集型的，容易出错，自上世纪50年代以来几乎没有发展。一项基于一种或多种代谢物信号（或信号组合）存在与否的新测试可以改善这一点，并为NHS节省成本。其次，如果我们的技术能够识别出精子能量分子中的缺陷，这就为进一步研究设计潜在的治疗方法提供了可能。我们建议，这可能通过以下四种方式中的一种或多种实现：(a)开发可在受孕前几周或几个月内由男性或女性服用的药物；(b)关于提高精子活力的特定食物或营养补充剂的建议；(c)开发刺激精子运动的润滑剂或子宫托，供夫妇在性交时使用；或(d)可用于体外受精和其他辅助受孕技术的精子活力刺激培养基。总之，我们认为我们的研究有可能更好地理解精子是如何制造和使用能量来游泳的。通过填补知识上的空白，通过在生育专家和放射科医生之间开展新的合作，我们认为我们有可能从根本上改变男性不育症的诊断和治疗。

Approximately 20% of young men have poor quality semen and in 50% of couples undergoing in vitro fertilisation (IVF) there is a problem with the sperm from the male partner. Whilst often the problem is because the male has a low sperm count, sometimes it is because his sperm don't swim very well. In such cases, sperm can be injected into his partner's eggs to help fertilisation happen (a process called Intra-cytoplasmic Sperm Injection or ICSI). But this adds to the cost of infertility treatment and is not always funded by the NHS. Currently there are no effective therapies to improve poor sperm motility, but to be able to give sperm a 'boost' might avoid the need for high-tech procedures such as ICSI in preference to less technical ones, or could avoid the need for assisted conception altogether if the therapy was very successful.Unfortunately we know very little about the way that sperm generate the energy necessary for their tail to beat and power them forwards. There are a number of ways they could do this and a range of different 'fuels' they could burn. Therefore, in this project, we propose to use some of the techniques developed by radiologists to examine the energy pathways used by cancer cells to develop new chemotherapy treatments. These techniques rely on detecting the molecular signature of atoms when they are placed in a magnetic field and are very similar to the technology used by doctors to scan a patient to see inside them (MRI). We have already developed a method to prepare sperm and place them inside the scanner and pilot data suggests that we can see key molecules involved in the production of sperm energy. In addition, we have also added some labelled 'fuels' to the sperm to watch how they use them. This suggests our techniques work and now we plan to undertake a more comprehensive analysis of sperm from different men.We will obtain semen from men with different fertilities and prepare their sperm to be scanned under different conditions. We will examine whether we can see differences in the molecules used to make and provide sperm energy between men whose sperm swim well and those whose sperm swim badly. In addition, we will also attempt to separate good swimming sperm from poor swimming sperm in the same man, to see if we can detect differences. If we can, then this may lead to two clinical developments.First, it may allow us to develop a better diagnostic test of sperm motility that is easier and cheaper to perform than the current method. At the moment, in order to diagnose male infertility related to poor sperm motility, a scientist has to observe the motility of sperm using a light microscope. This is labour intensive, prone to error and has developed little since the 1950s. A new test based on the presence or absence of one of more metabolite signals (or combination of signals) could improve this and lead to cost savings for the NHS.Second, if our techniques are able to identify deficiencies in the sperm energy molecules, this opens up the possibility of undertaking further research to devise potential cures. We suggest that this might be possible through one or more of the following four ways: (a) developing drugs that could be taken by the man or woman in the weeks and months prior to conception; (b) advice about specific foods or nutritional supplements to enhance sperm motility; (c) the development of sperm-motility stimulating lubricants or pessaries that could be used by the couple during sex; or (d) sperm-motility stimulating culture media that could be used in IVF and other assisted conception technologies.In conclusion, we propose that our research has the potential to provide a better understanding of how sperm make and use energy to swim. By filling that gap in knowledge, and by developing a new collaboration between fertility specialists and radiologists, we think we have the potential to radically change the diagnosis and treatment of male infertility.