"Physical and Chemical Cues that Guide Sperm Migration"

描述(申请人提供)：我们工作的长期目标是了解受精所需的精子与女性生殖道的相互作用。在美国，大约7%的已婚夫妇会受到不孕不育的影响，过去几年，养牛业的人工授精成功率一直在下降。滴虫病等性传播疾病(STD)是人类和牛的主要问题。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的迁移过程，可以开发出诊断和治疗不孕不育、防止性传播疾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，以确定促进精子迁移到卵子的生物物理和生化因素，但也抑制了性病病原体的上升，特别是那些导致滴虫病的病原体。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，因为公牛精子通过宫颈、输卵管连接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是确定引导精子在宫颈和输卵管交界处迁移的物理因素的作用。为实现这一目标，我们将实现以下分目标。1A.建立一个微流体模型，模拟宫颈和输卵管连接处通道的三个物理环境参数：主中心通道壁上的微通道、流体流动和流体粘弹性。1B.验证这样一种假设，即子宫颈和子宫输卵管交界处的微通道有助于精子在有流动的情况下向上游移动。作为研究的一部分，我们将探索液体粘弹性在促进精子逆流迁移方面的作用。1C。检验这样一种假设，即物理参数有利于精子进入微通道，而不是病原体，特别是滴虫胎儿。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在输卵管上的迁移。我们将验证这一假设，即精子蛋白结合蛋白(BSPs)的丢失和修饰在将精子从输卵管储存库释放到输卵管上部的过程中起着至关重要的作用。公牛精子与输卵管上皮细胞的结合是由精子上的3个BSP介导的，它们与输卵管上皮上的4个膜联蛋白(ANXA)相互作用。获能减少了结合，因此我们建议测试其对BSP的影响和对精子从输卵管上皮释放的影响，以及BSP与ANXAS的相互作用在将精子引导到卵子中所起的作用。

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.