"Physical and Chemical Cues that Guide Sperm Migration"

描述（由申请人提供）：我们工作的长期目标是了解精子与女性生殖道的相互作用，这是受精所必需的。在美国，大约7%的已婚夫妇患有不孕症，过去几年，养牛业人工授精的成功率一直在下降。滴虫病等性传播疾病是人类和牛的一个主要问题。最后，人类需要更安全的避孕方式。了解精子和病原体通过女性生殖道迁移的过程，有助于开发诊断和治疗不孕症、预防性病和防止意外怀孕的新方法。我们提出了一种独特的双管齐下的方法，以确定促进精子向卵子迁移的生物物理和生化因素，同时也抑制性病病原体的增加，特别是引起滴虫病的病原体。对于这个项目，牛模型不仅将为养牛业提供有用的信息，也将为人类医学提供有用的信息，因为公牛精子通过子宫颈、子宫输卵管交界处和输卵管迁移的生物物理和生化方面与人类非常相似。目的1是确定引导精子在子宫颈和子宫输卵管交界处迁移的物理因素的作用。为此，我们将开展以下工作。1一个。开发一个微流体模型，模拟子宫颈和子宫输卵管交界处通道物理环境的三个参数：主要中心通道壁上的微通道、流体流动和流体粘弹性。1 b。检验子宫颈和子宫输卵管交界处壁上的微通道在有水流的情况下帮助精子向上游移动的假设。作为研究的一部分，我们将探讨液体粘弹性在促进精子在流动中迁移中的作用。1 c。验证物理参数有利于精子进入微通道的假设，而不是病原体，特别是毛毛单胞菌的进入。目的2是阐明参与精子与输卵管上皮结合的分子如何调节精子向输卵管迁移。我们将验证精子结合蛋白（Binder of Sperm proteins, BSPs）的丢失和修饰在精子从输卵管储存库向输卵管上部释放过程中起关键作用的假设。牛精子与输卵管上皮的结合是由精子上的3种BSPs介导的，这些BSPs与输卵管上皮上的4种膜联蛋白（ANXAs）相互作用。因此，我们建议测试其对BSPs和精子从输卵管上皮释放的影响，以及BSPs与ANXAs的相互作用在引导精子进入卵子中的作用。

DESCRIPTION (provided by applicant): The long-term goal of our work is to understand the interactions of sperm with the female reproductive tract that are required for fertilization. Infertility affects about 7% of married couples in the US and the success rate of artificial insemination in the cattle industry has been dropping over the past several years. Sexually transmitted diseases (STDs) such as trichomoniasis are a major problem for both humans and cattle. Lastly, safer forms of contraception are needed for humans. Understanding the processes of sperm and pathogen migration through the female reproductive tract could enable the development of new methods for diagnosing and treating infertility, protecting against STDs, and preventing unwanted pregnancies. We are proposing a unique two-pronged approach to identify biophysical and biochemical factors that promote sperm migration to the egg but also inhibit the rise of STD pathogens, particularly those causing trichomoniasis. For this project, the bovine model will not only provide useful information to the cattle industry but also to human medicine, because biophysical and biochemical aspects of the migration of bull sperm through the cervix, uterotubal junction, and oviduct are quite similar to those of humans. Aim 1 is to identify roles of physical factors that guide sperm migration in the cervix and uterotubal junction. To achieve this, we will carry out the following subaims. 1A. Develop a microfluidic model that mimics three parameters of the physical environments of the passages in the cervix and uterotubal junction: the microchannels in the walls of the main central channel, fluid flow, and fluid viscoelasticity. 1B. Test the hypothesis that microchannels in the walls of the cervix and uterotubal junction assist sperm in moving upstream in the presence of a flow. As part of the investigation, we will explore the roles of fluid viscoelasticity in facilitating sperm migration against the flow. 1C. Test the hypothesis that physical parameters facilitate the entry of sperm into the microchannels in preference to entry of pathogens, particularly Tritrichomonas foetus. Aim 2 is to elucidate how the molecules involved in binding sperm to oviductal epithelium regulate sperm migration up the oviduct. We will test the hypothesis that loss and modification of Binder of Sperm proteins (BSPs) play crucial roles in releasing sperm from the oviductal storage reservoir toward the upper oviduct. Binding of bull sperm to oviductal epithelium is mediated by 3 BSPs on sperm, which interact with 4 annexin proteins (ANXAs) on the oviductal epithelium. Binding is reduced by capacitation, so we propose to test its effects on BSPs and on release of sperm from oviductal epithelium, as well as the role that the interactions of BSPs with ANXAs could play in guiding sperm to the egg. PUBLIC HEALTH RELEVANCE: Infertility affects about 7% of married couples in the US and, although artificial reproductive technologies have done much to alleviate this problem, there are health risks and stress involved in undergoing diagnosis and treatment. Other reproductive health problems are (1) contraceptives are not as safe or effective as they might be, and (2) sexually transmitted diseases (STDs). Understanding the processes of sperm and pathogen migration through the female reproductive tract could enable the development of new methods for diagnosing and treating infertility, protecting against STDs, and preventing unwanted pregnancies.