Polycystins and Male Fertility

描述（由申请人提供）：成功受精需要精子在可育状态下到达卵母细胞；因此，获得能力的过程代表了男性生育能力的一个关键方面。尽管体外研究已经确定了精子中一系列关键的生化状态变化，这些变化与获得能态有关，但在女性生殖道内运作的机制及其时间尚不清楚。因此，尽管女性生殖道在控制精子获能方面发挥着重要作用，但这些调节事件的生化基础仍有待研究。缺乏生殖系限制性多囊蛋白pkdrej的小鼠在体外和体内均表现出精子行为的改变，这与获能过程调节的变化一致。表型方面的鉴定似乎改变了突变小鼠在雌性生殖道内精子的行为，这表明这些动物将成为阐明精子在输卵管内运输受到调节的机制的有用工具。目前的建议旨在建立在我们初步观察的基础上，更详细地探讨多囊蛋白pkdrej在调节男性生育能力方面所起的作用。这项提议有两个目的。1)检查为什么与野生型雄性精子相比，这些精子到达卵母细胞的数量减少。这个目标将包括检查精子在女性生殖道内的运动。2)利用体外获能试验确定缺乏pkdrej的男性精子行为改变的可能生化基础。在避孕或治疗不孕症方面向个人提供生育控制是一个基本的健康问题。影响配子在雌性生殖道内运动的因素是决定生殖能力的关键因素。了解控制这些过程的因素及其所针对的信号通路可能为控制受精和不孕症的治疗策略提供新的靶点。

DESCRIPTION (provided by applicant): Successful fertilization requires the arrival of the spermatozoa at the oocyte in a fertile state; the process of capacitation thus represents one of the key aspects of male fertility. Although in vitro studies have identified a key series of biochemical state changes in spermatozoa which correlate with the acquisition of the capacitated state, the mechanisms which operate within the female reproductive tract, and their timing, are less clear. So while the female reproductive tract plays important roles in control of sperm capacitation, the biochemical basis of these regulatory events remain to be characterized. Mice which lack the germ line restricted polycystin pkdrej show alterations in sperm behavior, both in vitro and in vivo which are consistent with changes in the regulation of the capacitation process. The identification of aspects of the phenotype which appear to alter the behavior of sperm from mutant mice within the female tract suggests that these animals will be a useful tool to elucidate the mechanisms by which sperm transport within the oviduct is regulated. The current proposal aims to build on our preliminary observations and address in more detail the role the polycystin pkdrej plays in the regulation of male fertility. This proposal has two aims. 1) Examine why reduced numbers of these sperm reach the oocyte when compared to sperm from wildtype males. This aim will involve examining the movement of sperm within the female reproductive tract. 2) The use of in vitro capacitation assays to determine a possible biochemical basis for the altered behavior of sperm from males lacking pkdrej. Providing individuals with control of their fertility either in the context of contraception or in the treatment of infertility is a fundamental health issue. The factors affecting the movement of gametes within the female reproductive tract represent a key determinant of fertility. Understanding the factors that control these processes and the signaling pathways they target may provide new targets both for the control of fertilization and as a treatment strategy for infertility.