Developing an animal model to identify the role of the sperm centriole in fertility

开发动物模型来确定精子中心粒在生育能力中的作用

• 批准号: 9372723
• 负责人: Tomer Avidor-Reiss
• 金额: $ 22.46万
• 依托单位: UNIVERSITY OF TOLEDO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-11 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9372723
• 关键词: Address; Animal Model; Animals; Area; Basic Science; Biochemistry; Biological Models; Cells; Centrioles; Centrosome; Characteristics; Collaborations; Data; Daughter; Development; Disease; Distal; Drosophila genus; Electron Microscopy; Embryonic Development; Fertility; Fertilization; Gene Transfer Techniques; Genetic; Genetic Models; Goals; Human; Infertility; Inherited; Insecta; Knowledge; Label; Letters; Male Infertility; Mammalian Genetics; Mammals; Mitosis; Mitotic; Modeling; Mus; National Institute of Child Health and Human Development; Oryctolagus cuniculus; Pregnancy loss; Property; Proteins; Rattus; Recruitment Activity; Research; Resolution; Role; Somatic Cell; Spermatids; Spermiogenesis; Spontaneous abortion; Structure; Study models; System; Testing; Time; Transgenic Organisms; base; design; fly; innovation; insight; light microscopy; sperm cell; sperm function; zygote

Somatic cells require two centrioles that each form one of the spindle poles of dividing cells. In contrast, the zygotes of insects and many mammals, including humans, are thought to have only a single centriole, which is of paternal origin. The Avidor-Reiss lab has identified a second, atypical centriole of paternal origin in insect zygotes that is essential for normal embryo development. More importantly, they have acquired new data suggesting that, like in insects, the spermatozoa of humans and many other mammalian species have an atypical centriole that may also be paternally inherited. Consequently, the long-term goal of the proposed research is to reveal the unique properties of these atypical sperm centrioles, specifically their conservation, unique biochemistry, function, and contribution to fertilization and embryo development. The objective of this application is to (1) test if the distal centriole of mammalian sperm, which is thought to be “degenerated” and functionally dead, is actually an “atypical” centriole that is essential after fertilization and (2) to develop a mammalian model system to study the role of this “degenerated” distal centriole during embryo development. Data from the Avidor-Reiss lab indicates that mammalian spermatozoa contain, in addition to the typical centriole (known as the proximal centriole), an atypical centriole (the “degenerated” distal centriole). These data suggest that the distal centriole is not degenerated, but rather remodeled. This atypical centriole lacks the structural characteristics of a centriole, but contains core centriolar proteins. Therefore, the central hypothesis is that, like the proximal centriole, the remodeled distal centriole (RDC) forms one of the two zygotic centrosomes after fertilization and one of the spindle poles when the zygote divides. The rationale is that the identification of the RDC as the mammalian second zygotic centriole will direct studies of its role in male infertility and early pregnancy loss. The rabbit is an excellent model for these studies because rabbit zygotes, like humans, require sperm centrioles. Our specific aim is to determine the origin, number, and structure of the centrioles in the rabbit zygote. This research is innovative because it is the first to examine a revolutionary hypothesis on the origin of the second zygotic centriole, using a mammalian model specifically designed for this purpose. This study is expected to advance the understanding of centriolar function in fertility. Ultimately, knowledge gained from this basic research will form a basis for additional insights into potential new causes of male infertility, early stage miscarriages, and developmental diseases.

体细胞需要两个中心粒，每个中心粒形成分裂细胞的一个纺锤极。而反观 昆虫和许多哺乳动物（包括人类）的受精卵被认为只有一个中心粒， 父亲的起源。Avidor-Reiss实验室在昆虫中发现了第二个非典型的父系起源中心粒 受精卵是胚胎正常发育所必需的。更重要的是，他们获得了新的数据 这表明，像昆虫一样，人类和许多其他哺乳动物的精子也有一个 也可能是父系遗传的非典型中心粒。因此，拟议的长期目标 研究的目的是揭示这些非典型精子中心粒的独特性质，特别是它们的保守性， 独特的生物化学，功能和对受精和胚胎发育的贡献。的目的 应用是（1）测试哺乳动物精子的远端中心粒，其被认为是“退化的”， 功能死亡，实际上是一个“非典型”的中心粒，是受精后必不可少的，（2）发展一个 哺乳动物模型系统来研究这种“退化”的远端中心粒在胚胎发育过程中的作用。 Avidor-Reiss实验室的数据表明，哺乳动物精子除了含有典型的 中心粒（称为近端中心粒），非典型中心粒（“退化”远端中心粒）。这些 数据表明，远端中心粒不是退化的，而是重塑的。这种非典型中心粒缺乏 中心粒的结构特征，但含有核心中心粒蛋白。因此，中心假设 与近端中心粒一样，重塑的远端中心粒（RDC）形成两个合子之一， 受精后的中心体和受精卵分裂时的一个纺锤体极。理由是， 将RDC鉴定为哺乳动物第二合子中心粒将指导其在雄性中作用的研究 不孕症和早孕丢失。 兔子是这些研究的极好模型，因为兔子的受精卵和人类一样，需要精子 中心粒我们的具体目标是确定兔子中心粒的起源、数量和结构 受精卵这项研究是创新的，因为它是第一次审查一个革命性的假说的起源， 第二合子中心粒，使用专门为此目的设计的哺乳动物模型。本研究 有望促进对生育中心粒功能的理解。最终，从这方面获得的知识 基础研究将为进一步深入了解男性不育的潜在新原因奠定基础， 流产和发育性疾病。