Reproductive Genomics: Mutant Models for Infertility

生殖基因组学：不孕不育的突变模型

• 批准号: 7877683
• 负责人: JOHN J EPPIG
• 金额: $ 0.48万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2010-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7877683
• 关键词: Reproductive; Genomics; Mutant; Models; Infertility

DESCRIPTION (provided by applicant): 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. Relevance to Public Health: This Program Project will help establish the etiology for what are now poorly understood and untreatable cases of human infertility. By defining mechanisms of gametogenesis, the program will contribute to still rudimentary knowledge of what constitutes a "good" gamete, and thereby help establish standards guiding assisted reproductive technologies. Finally, by resolving mechanisms for mutations whose sole phenotype is infertility, the program will contribute to the basic knowledge foundation that underpins management of both fertility and infertility.

描述（由申请人提供）：在过去的五年中，杰克逊实验室的重生程序计划生产了新颖的不育突变模型，作为生殖生物学家社区的资源。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约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，通过在该程序中生成X-Link-Link-Link-Link-Link-Link-Link-Link-Link-Link-Link-Link-Link-Link-Link-Link-Link-Link-Link-Link-Link-Link-Link-Link-new for in Progence in New In new Programe。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X染色体上的突变的方法生产突变模型将为资源增加深度，并且这些突变将具有进一步的科学重要性，因为X染色体从未针对前向ENU诱变筛选。 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。 与公共卫生的相关性：该计划项目将有助于建立病因，以了解现在对人类不孕症的理解和不可治疗的案例。通过定义配子发生的机制，该计划将有助于仍然对构成“良好”配子的基本知识有助于建立指导辅助生殖技术的标准。最后，通过解决唯一表型是不育的突变的机制，该计划将有助于基础知识基础，从而支持生育和不育的管理。