Understanding sperm membrane roles in male fertility

了解精子膜在男性生育能力中的作用

• 批准号: RGPIN-2020-07186
• 负责人: Buhr, Mary
• 金额: $ 2.04万
• 依托单位: University of Saskatchewan
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=743519
• 关键词: Understanding; sperm; membrane; roles; male

The molecules in the head of mammalian sperm must reorganise just prior to meeting the egg, in order to fertilise it. This reorganisation is started by signals that the sperm receives that cause the sperm to reorganise the membrane structure of its head and start specific internal reactions that enable the sperm to bind to and penetrate the egg. The exact nature of the signal(s), and how they are received, is unknown, making it difficult to improve the fertility of the male or to preserve sperm for artificial insemination. One molecule, Na/K-ATPase, is well known as an enzyme but recently was recognised as a membrane-bound signal receptor in some body cells. We showed that it also acts in sperm as a membrane receptor, sending signals into the sperm to start capacitation when its specific hormone ouabain binds to it. Na/K-ATPase is made of two subunits, each of which has several isoforms. Think of the isoforms of one subunit desktop, laptop or ipad computer, each requiring somewhat different methods to turn them on. The other subunit is a peripheral device, either a printer, scanner or webcam. Pairing any one computer isoform with any one peripheral isoform affects the function of the paired devices, and certainly changes its output. Similarly, isoforms and subunits in sperm Na/K-ATPase affect how it functions, and we hypothesize that good fertility really depends on having the correct pair of isoforms to have Na/K-ATPase perform optimally as a signal-receptor, just as you need to pair the correct computer and peripheral device to function smoothly, and efficiently produce the high-quality output you want. Since the subunits are proteins, and it is the membrane over the head of the sperm that first binds to the egg and where capacitation starts, over the 5 years of the research we will compare the specific amino acid structure of the subunits in the head membrane of sperm from high- and low-fertility bulls to identify which pairing is associated with the best fertility; whether it is the amount of isoform, or its structure, that influences fertility; and we will follow the signal's activation path in the sperm that ultimately permits fertilization. This serves the long-term objective, to be able to explain currently unexplained causes of infertility, to understand and be able to better protect, predict and improve sperm membrane molecules that impact fertility of sperm. Results will enable us to detect males with poor chances of fertility, and to design remediation methods that will protect those critical sperm membrane molecules. This will enhance reproductive success for domestic and endangered species, and potentially find application in human reproduction.

哺乳动物精子头部的分子必须在与卵子相遇之前重组，以使其受精。这种重组是由精子接收到的信号启动的，这些信号导致精子重组其头部的膜结构，并启动特定的内部反应，使精子能够结合并穿透卵子。这些信号的确切性质以及它们是如何被接收的尚不清楚，这使得很难提高男性的生育能力或保存精子进行人工授精。其中一种分子Na/K-ATP酶是众所周知的酶，但最近被认为是某些身体细胞中的膜结合信号受体。我们发现，它也作为一个膜受体在精子中，发送信号到精子开始获能时，其特定的激素哇巴因结合到它。Na/K-ATP酶是由两个亚基，其中每一个有几个亚型。想象一下，一个子单元是台式机、笔记本电脑或iPad电脑，每个子单元需要不同的方法来启动它们;另一个子单元是外围设备，打印机、扫描仪或网络摄像头。将任何一个计算机异构体与任何一个外围设备异构体配对都会影响配对设备的功能，当然也会改变其输出。同样，精子Na/K-ATP酶中的亚型和亚基会影响它的功能，我们假设良好的生育能力真的取决于拥有正确的亚型对，使Na/K-ATP酶作为信号受体发挥最佳作用，就像你需要配对正确的计算机和外围设备才能顺利运作，并有效地产生你想要的高质量输出一样。由于这些亚基是蛋白质，并且是精子头部的膜首先与卵子结合，并且是获能开始的地方，在5年的研究中，我们将比较高生育力和低生育力公牛精子头部膜中亚基的特定氨基酸结构，以确定哪一对与最佳生育力相关;无论是同种型的数量，还是它的结构，都会影响生育能力;我们将跟踪精子中最终允许受精的信号激活路径。这有助于长期目标，能够解释目前无法解释的不育原因，理解并能够更好地保护，预测和改善影响精子生育力的精子膜分子。研究结果将使我们能够检测出生育能力差的男性，并设计出保护这些关键精子膜分子的补救方法。这将提高家养和濒危物种的繁殖成功率，并可能在人类繁殖中找到应用。