Reproductive Genomics: Mutant Models for Infertility

生殖基因组学：不孕不育的突变模型

• 批准号: 8090002
• 负责人: JOHN J EPPIG
• 金额: $ 23.62万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8090002
• 关键词: Address; Affect; Assisted Reproductive Technology; Bromodomain; Communities; Development; Embryo; Ethylnitrosourea; Etiology; Fertility; Foundations; Funding; Gametogenesis; Gene Family; Gene Mutation; Genes; Genetic Models; Genomics; Germ Cells; Goals; Harvest; Human; Infertility; Investigation; Knowledge; Laboratories; Link; Maps; Meiosis; Methods; Modeling; Mus; Mutagenesis; Mutation; Oocytes; Other Genetics; Pathway interactions; Phenotype; Philosophy; Production; Prophase; Public Health; Recording of previous events; Recovery; Reproduction; Research; Research Personnel; Resources; Scheme; Spermatocytes; Study models; Time; Transcriptional Regulation; X Chromosome; chromatin remodeling; gene cloning; mutant; new technology; novel; positional cloning; programs; reproductive; success

For the past five years, the ReproGenomics Program at The Jackson Laboratory has produced novel mutant models of infertility as a resource for the community of reproductive biologists. The mutations produced and mapped by this program in this relatively short period of time represent -10% of the total infertility mutations documented throughout the history of mouse research. These efforts have generated a unique resource of models for the study of gonadogenesis, gametogenesis, meiosis, and gamete function. The objectives of this continuation application are to 1) utilize ReproGenomics mutant models, as well as other genetic models, for investigation of several themes underlying gametogenesis that were generated and characterized in this program, and 2) expand the depth and breadth of the resource by generating additional autosomal mutations, plus X-linked mutations derived using new technology developed in the Program. The focus of Project I is on a gene family expressing bromodomains and involved in chromatin remodeling and/or transcriptional control during gametogenesis; the focus of Project II is on critical aspects of early meiotic prophase in spermatocytes; and the focus of Project III is on the oocyte-to-embryo transition. Core A will continue successful production of autosomal ENU-induced infertility phenotypes as well as a novel resource of X-linked infertility mutations, and Core B will conduct fine mapping and positional cloning of selected mutations. Production of mutant models by a method selecting mutations on the X chromosome will add depth to the resource, and these mutations will be of further scientific importance because the X chromosome has never been targeted in forward ENU mutagenesis screens. The program will continue to encourage other researchers in the community of reproductive biologists to study the mutations already and yet to be produced. This Program Project 1) provides community resources, 2) is a framework for totally unbiased discovery research that will enable new directions by other investigators, and 3) addresses important questions about gametogenesis using novel mutant models with relevant phenotypes that were produced in the Program Project.

在过去的五年中，杰克逊实验室的重生程序计划为生殖生物学家社区提供了新颖的不育模型作为资源。该程序在此相对较短的时间内产生和映射的突变占小鼠研究史上记录的总不育突变的-10％。这些努力为研究性发生，配子发生，减数分裂和配子功能的模型提供了独特的资源。 该延续应用的目标是1）使用重生突变模型以及其他遗传模型，以研究该程序中生成和表征的几个主题，以及2）扩大资源的深度和广度。 附加常染色体突变，以及使用该程序中开发的新技术得出的X连锁突变。项目I的重点放在表达溴结构域的基因家族上，并参与配子发生过程中的染色质重塑和/或转录控制。第二个项目的重点是精子细胞早期减数分裂预言的关键方面。项目III的重点放在卵母细胞到embryo的过渡上。核心A将继续成功产生常染色体ENU诱导的不育症表型以及X连锁不孕突变的新资源，而Core B将进行精细的映射和精细的映射和位置克隆。通过选择突变的方法生产突变模型 X染色体将为资源增加深度，这些突变将具有进一步的科学重要性，因为X染色体从未在正向ENU诱变筛选中靶向。 该计划将继续鼓励生殖生物学家社区中的其他研究人员已经研究了这些突变，尚未生产。该计划项目1）提供社区资源，2）是一个完全无偏见的发现研究的框架，该研究将使其他研究人员的新方向以及3）使用与计划项目中生产的相关表型的新型突变模型解决有关配子发生的重要问题。