A structural approach to understanding the role of the centrioles in human sperm

全球生育率的全面下降导致辅助生殖技术(ART)的使用增加。尽管对抗逆转录病毒治疗的需求增加，但成功率仍然很低(35岁以下女性的成功率为25%，年龄较大的女性甚至更低)，因此需要多个周期。正确诊断不孕症的原因可以提高抗逆转录病毒治疗的成功率。男性不育症是夫妻尝试抗逆转录病毒治疗的主要原因之一。然而，超过60%的男性不育被认为是特发性的，这突显出需要对精子生物学有更详细的了解。ART中最常用的方法之一是卵胞浆内单精子注射(ICSI)，即选择单个精子细胞并直接注射到卵母细胞中。然后，受精的卵母细胞可以被移植到子宫中发育成胚胎。卵胞浆内单精子注射的关键步骤是选择单个精子进行注射。通常这种选择的主要标准是大体形态，但ART的低成功率要求在ICSI之前使用新的工具和标准来评估精子质量。精子中心粒是完全负责协调第一次细胞分裂的细胞器，因为卵母细胞本身没有中心粒。因此，当精子中心粒或其结构受损时，会导致胚胎发育缺陷和妊娠损失。与体细胞相比，精子中心粒在精子成熟过程中经历了显著的重塑过程。该项目的主要目的是使用冷冻电子断层扫描技术提供人类精子中心粒的详细图像。将比较生育和不育患者成熟精子细胞中的中心粒以及早期精子细胞(未成熟精子细胞)中的中心粒。该项目将提供对具有生育能力的人类精子中心粒的详细分子理解。此外，它还可以识别导致男性不育的分子和结构细节，从而改善ICSI的精子选择。

An overall decline in fertility across the globe has led to an increase in the use of assisted reproductive technologies (ART). Despite the increased need for ART, the success rates are still low (<25% for women younger than 35 and even lower for older women), thus requiring multiple cycles. ART success rates can be improved with correct diagnosis of the cause of infertility. Male infertility is one of the major reasons for couples to attempt ART. However, more than 60% of male infertility is considered idiopathic, highlighting that there is a need for a more detailed understanding of sperm biology. One of the most frequently used approaches in ART is intracytoplasmic sperm injection (ICSI), in which a single sperm cell is selected and directly injected into an oocyte. The fertilized oocyte can then be transferred into the uterus to develop into an embryo. A crucial step in ICSI is the selection of a single sperm cell for injection. Often the main criteria for this selection is gross morphology but the low success rates in ART call for new tools and criteria to assess sperm quality before ICSI. Sperm centrioles are organelles that are entirely responsible to orchestrate the first cell division, as oocytes do not have centrioles of their own. Thus, when the sperm centrioles or their structure are impaired, this will lead to embryo development defects and pregnancy loss. Compared to somatic cells, sperm centrioles were shown to undergo a significant remodeling process during sperm maturation. The main aim of this project is to provide a detailed view of human sperm centrioles using cryo-electron tomography. Centrioles from mature sperm cells of fertile and infertile patients as well as centrioles in early spermatids (immature sperm cells) will be compared. The project will provide a detailed molecular understanding of fertile human sperm centrioles. In addition, it may allow the identification of molecular and structural details causing infertility in men and consequently improve sperm selection for ICSI.