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Signaling Mechanisms that Control Chromosome Segregation during Female Meiosis

女性减数分裂过程中控制染色体分离的信号机制

基本信息

批准号：
10332058
负责人：
Karen A Schindler
金额：
$ 2.04万
依托单位：
RUTGERS, THE STATE UNIV OF N.J.
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-17 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10332058
关键词：
Address Age Aging Anaphase Aneuploidy Area Biological Assay Biomedical Research Cell Division Process Cell Line Cellular biology Chromosome Pairing Chromosome Segregation Chromosomes Clinical Congenital Abnormality Data Diploidy Dissection Embryonic Development Ensure Family Family member Female Fertility Funding Genetic Genetic Transcription Germ Cells Goals Grant Haploidy Homologous Gene Human Image Infertility Kinetochores Knock-out Knockout Mice Knowledge Learning Light Malignant Neoplasms Maternal Age Maternal Messenger RNA Mediating Meiosis Mentors Microscopy Microtubules Mitosis Mitotic spindle Molecular Mouse Strains Mus National Institute of General Medical Sciences Nocodazole Oocytes Phenotype Phosphotransferases Premature aging syndrome Process Protein Kinase Proteins Proteomics RNA, Messenger, Stored Reproductive Biology Research Resolution Role Sequence Homology Sexual Reproduction Signal Transduction Sirtuins Sister Chromatid Spontaneous abortion Techniques Technology Testing Training Activity Translations Woman Work advanced maternal age age related aurora B kinase aurora kinase aurora kinase A egg falls imprint insight interest job market member multicatalytic endopeptidase complex oocyte quality precursor cell prevent proteostasis reproductive skills sperm cell tool

项目摘要

Project Summary Meiosis is the cell division process that is essential for sexual reproduction because it creates haploid gametes from diploid precursor cells. Chromosome segregation during meiosis I (MI) is unique because replicated sister chromatids remain attached to one another while homologous chromosome pairs segregate. In humans, mistakes in MI occur are strikingly high in female gametes (oocytes), resulting in infertility, miscarriage, or birth defects, yet the molecular mechanisms that control MI are poorly understood. Work in our lab has been instrumental in dissecting the signaling mechanisms used to control MI to explain this phenomenon. The Aurora protein kinase family is comprised of three members: AURKA, AURKB and AURKC. The AURKs are essential regulators of chromosome segregation in mitosis, and their activities are required for completing MI chromosome segregation. AURKC expression is limited to gametes and is aberrantly expressed in some cancers. Yet, because AURKC shares high sequence homology with AURKB standard approaches to understand their MI-specific functions were not sufficient. Our expertise in creating and evaluating oocyte- specific AURK knockout mice has afforded us the ability to unravel the mystery of why oocytes contain two kinases that are similar to one another. Not only have we identified AURKB and AURKC functions that are distinct from one another, we have discovered that the three AURKs regulate one another. In this proposal, we aim to continue to dissect the requirements for each AURK during MI, and to determine how and why the AURKs regulate one another. By studying the functions of all three AURK family members, we will uncover the evolutionary benefit and the consequences of expressing three AURKs. To do so we will: 1) Elucidate how AURKA and AURKC counter-acting activities are required to build an MI spindle, 2) examine cell lines that aberrantly express AURKC to determine if these counter-acting activities drive aneuploidy in mitosis, and 3) determine how AURKB regulates proteins required for the spindle assembly checkpoint during MI. Information gained from our studies will help us fully understand how these kinases operate during MI while highlighting distinct differences between how mitosis and MI are controlled. Importantly, these data will shed light on how MI chromosome segregation is controlled in oocytes and why it commonly goes awry in women leading to aneuploidy.

项目总结