Molecular Marker for Centriole Remodeling in Human Reproduction

人类生殖中中心粒重塑的分子标记

• 批准号: 10011841
• 负责人: Tomer Avidor-Reiss
• 金额: $ 7.53万
• 依托单位: UNIVERSITY OF TOLEDO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-06 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10011841
• 关键词: Affect; Animals; Cattle; Cells; Centrioles; Centrosome; Cilia; Cytoplasmic Structures; Data; Defect; Development; Diagnosis; Diagnostic tests; Disease; Distal; Embryo; Embryonic Development; Fathers; Fertilization; Genetic; Goals; Habitual Abortion; Human; Immunofluorescence Immunologic; Infertility; Inherited; Knowledge; Laboratories; Male Infertility; Microscopy; Microtubules; Modeling; Morphology; Names; Neck; Organelles; Outcome; Procentriole; Process; Proteins; Reproduction; Research; Rod; Role; Signal Transduction; Sperm Tail; Spermatids; Spermiogenesis; Spontaneous abortion; Structural Protein; Structure; Testing; Time; base; blastomere structure; cell motility; developmental disease; diagnostic biomarker; early pregnancy loss; fly; improved; in vitro Assay; innovation; molecular marker; reconstitution; recruit; reproductive; sperm cell; sperm morphology; sperm quality; tool; zygote

Summary The centrioles are the only cytoplasmic structures provided exclusively by the sperm, to the embryo. Centrioles are microtubule-based organelles that have two critical functions. They form the cell’s cilium (a subcellular mechanism for signaling and motility). And together with the proteinaceous pericentriolar material (PCM), they form the cell’s centrosome (the cell’s major microtubule organization center). Dividing embryonic cells must have precisely two centrioles for healthy development. During sperm formation, the quantity of many centriolar and PCM proteins declines, modifying the structure of one of the sperm centrioles beyond recognition. This process is known as centrosome reduction and is thought to eliminate the PCM and degenerate one of the centrioles, leaving the sperm with one intact centriole. The presence of only one recognizable centriole raises the question, what is the origin of the embryo’s second centriole? Recently, the Avidor-Reiss laboratory determined that the presumed degenerated centriole is unexpectedly maintained, despite structural and protein compositional changes. Furthermore, the Avidor-Reiss lab characterized the sperm neck and found that all centrosomal structures had altered protein compositions. They named the structural changes, protein enrichment, and protein reduction, as Centriole Remodeling. The role and importance of centriole remodeling in humans are poorly understood. However, evidence from the Avidor-Reiss lab argues that remodeling is essential for embryo development in animals. Currently, a significant fraction of reproductive diseases, such as infertility, recurrent miscarriages, and abnormal embryo development, are of unknown cause. Since the Avidor-Reiss lab recently found that the remodeled sperm centrioles function in the zygote, errors in centriole remodeling may be a previously unknown cause for reproductive diseases. Consequently, the long-term goal of the proposed research is to develop a diagnostic test for reproductive diseases caused by sperm centriole defects. The objective of this application is to determine the first set of centriole remodeling markers that are associated with defective sperm. The central hypothesis of our research is that abnormal levels of centriole remodeling proteins in the spermatozoon can cause reproductive diseases. The specific aim of this application is to identify centriolar markers that are associated with abnormal sperm morphology and infertility. This research is conceptually innovative because it is the first study that aims to identify centriole remodeling proteins for the diagnosis of reproductive diseases. The rationale is that the identification of diagnostic markers that are involved in centriole remodeling will provide an essential step towards identifying new causes of reproductive diseases. Ultimately, knowledge gained from this research has the potential to improve the diagnosis and treatment of diseases such as idiopathic male infertility, early pregnancy loss, and embryo development defects.

摘要 中心粒是唯一专门由精子提供给胚胎的细胞质结构。 中心粒是以微管为基础的细胞器，具有两个关键功能。它们形成了细胞的纤毛 (一种信号和运动的亚细胞机制)。并与蛋白质类中心周围物质一起 (PCM)，它们形成细胞的中心体(细胞的主要微管组织中心)。分裂胚胎 细胞必须恰好有两个中心粒才能健康发育。 在精子形成过程中，许多中心粒和PCM蛋白的数量下降，从而改变了精子的结构 其中一个精子中心粒面目全非。这一过程被称为中心体减少，被认为 以消除PCM并使其中一个中心粒退化，留下一个完整的中心粒。 只有一个可识别的中心粒的存在提出了一个问题，胚胎第二个中心粒的起源是什么？ 中心粒？最近，Avidor-Reiss实验室确定假定的退化中心粒是 出人意料地保持着，尽管结构和蛋白质组成发生了变化。此外，Avidor-Reiss Lab对精子颈进行了特征分析，发现所有中心体结构都改变了蛋白质成分。 他们将这种结构变化、蛋白质丰富和蛋白质减少称为中心粒重塑。这个 人类对中心粒重塑的作用和重要性知之甚少。然而，来自 Avidor-Reiss实验室认为，重塑对动物的胚胎发育至关重要。 目前，相当一部分生殖疾病，如不孕不育、反复流产和异常 胚胎发育，原因不明。因为Avidor-Reiss实验室最近发现改装的 精子中心粒在受精卵中发挥作用，中心粒重塑的错误可能是以前未知的原因 生殖疾病。因此，拟议研究的长期目标是开发一种诊断 检测由精子中心粒缺陷引起的生殖疾病。此应用程序的目标是 确定与缺陷精子相关的第一组中心粒重塑标记物。中环 我们研究的假设是精子中中心粒重塑蛋白的异常水平可以 导致生殖疾病。这项应用的具体目的是识别中心粒标志物 与精子形态异常和不育症有关。这项研究在概念上是创新的，因为它 是第一个旨在确定用于诊断生殖疾病的中心粒重塑蛋白的研究。 其基本原理是，识别参与中心粒重塑的诊断标志物将提供 这是确定生殖疾病新原因的重要一步。归根结底，从 这项研究有可能改善特发性男性等疾病的诊断和治疗 不孕症、早孕丢失和胚胎发育缺陷。