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元素，每个中心元素形成分裂细胞的主轴杆之一。相反， 人们认为昆虫和许多哺乳动物（包括人类）的Zygotes只有一个中心 父亲起源。 Avidor-Reiss实验室已经确定了昆虫中的第二个非典型的父亲起源 对正常胚胎发育至关重要的合子。更重要的是，他们获得了新数据 表明，与昆虫一样，人类和许多其他哺乳动物的精子具有 非典型的中心，也可能是父亲遗传的。因此，提案的长期目标 研究是为了揭示这些非典型精子中心元素的独特特性，特别是它们的保护， 独特的生物化学，功能以及对受精和胚胎发育的贡献。这个目的 应用是（1）测试哺乳动物精子的远端中心，被认为是“退化”和 在功能上死亡，实际上是一个“非典型”中心，是受精后必不可少的，（2）发展 哺乳动物模型系统研究在胚胎发育过程中这种“退化”远端中心的作用。 来自Avidor-Reiss实验室的数据表明，除了典型 Centriole（称为近端中心），一种非典型中心（“退化”远端中心）。这些 数据表明，远端中心未退化，而是重塑。这个非典型的中心缺乏 中心的结构特征，但含有核心中心蛋白。因此，中心假设 是，像近端中心一样，重塑的远端中心（RDC）形成了两个合子之一 施肥后的中心体和合子分裂时的纺锤杆之一。理由是 将RDC鉴定为哺乳动物第二个二拟合中心，将指导其在男性中的作用 不育和早期妊娠丧失。 兔子是这些研究的绝佳模型，因为兔子像人类一样需要精子 我们的具体目的是确定兔子中心元的起源，数量和结构 合子。这项研究具有创新性，因为它是第一个研究有关起源的革命性假设 第二个合子中心，使用专门为此目的设计的哺乳动物模型。这项研究是 预计会推进对生育能力中的中心功能的理解。最终，从中获得的知识 基础研究将构成对潜在的男性不育症的潜在新原因的额外见解的基础 流产和发展疾病。