Reproductive Genomics: Mutant Models for Infertility

生殖基因组学：不孕不育的突变模型

• 批准号: 6623364
• 负责人: JOHN J EPPIG
• 金额: $ 99.82万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6623364
• 关键词: fertility; functional /structural genomics; gametogenesis; genetic models; laboratory mouse; model design /development; mutant

This Program Project will develop an unprecedented resource for mammalian reproductive biologists: mutant mouse models of infertility. The approach will be to induce mutations in mice that cause infertility, map them, and provide a morphological, functional, and molecular characterization of phenotype. The proposed strategy will reap a spectrum of mutations affecting virtually all aspects of reproductive function, including neuroendocrine and behavioral aspects, but especially gonadogenesis, gametogenesis, meiosis, ovulation, fertilization and early embryo development. While some of these are of interest to the PIs of this Program, an important goal of this Program is to provide resources to the scientific community of reproductive biologists. The Mutagenesis and Phenotypic Screening Core will conduct a large-scale, whole-genome mutagenesis program to screen for recessive mutations in the third progeny generation. The primary screen will be to mater mice; females that fail to become pregnant and males that fail to make females pregnant will be subjected to a secondary screen that includes gonad histology and assessment of sperm and egg function. Heritability of reproductive defects will be confirmed by the Core and sperm from carrier males will be archived by cryopreservation. Mutants will be made available to the scientific community via the Program Project Website and the distribution facilities of The Jackson Laboratory. Mutations affected gametogenesis will be mapped in Project by Schimenti to facilitate colony maintenance and as a first step in gene cloning. The focus on Project by Schimenti will be on mutations affected meiotic recombination and chromosome metabolism; these will be mapped in Project by Schimenti to facilitate colony maintenance and as a first step in gene cloning. The focus of Project by Schimenti will be on mutations affecting meiotic recombination and chromosome metabolism; these will be mapped to high resolution and a subset will be positionally cloned. Projects by Handel and Eppig will carry out phenotype analysis of mutants impaired in spermatogenesis or sperm function, and in oogenesis or oocyte function, respectively. Additionally, a set of marker gene sequences will be developed in Projects providing a resource of molecular analysis of gametogenesis and germ cell-somatic cell communication. These marker genes will be essential for profiling gene expression during gametogenesis in mutants, providing a molecular phenotype that gives information about stage of arrest as well as of downstream sequences of mutant gene actions. Taken together, the mutagenesis program, mapping and detailed mutant phenotype analyses will provide to the scientific community unparalleled resources for understanding mammalian gametogenesis and bringing new understanding to causes of human infertility

该计划项目将为哺乳动物生殖生物学家开发前所未有的资源：不育的突变小鼠模型。该方法将是诱导导致不育，绘制它们的小鼠突变，并提供表型的形态，功能和分子表征。所提出的策略将获得一系列突变，影响生殖功能的几乎所有方面，包括神经内分泌和行为方面，尤其是性别生成，配子发生，减数分裂，排卵，受精和早期胚胎发育。尽管其中一些对该计划的PI感兴趣，但该计划的一个重要目标是为生殖生物学家的科学界提供资源。诱变和表型筛选核心将进行大规模的全基因组诱变程序，以筛选第三个后代生成中隐性突变。主要的屏幕将是mater小鼠；未能怀孕的女性，未能使女性怀孕的男性将受到次要筛查，其中包括性腺组织学和精子和卵功能的评估。生殖缺陷的遗传力将由核心证实，而男性载体将通过冷冻保存存档。突变体将通过计划项目网站和杰克逊实验室的分销设施提供给科学界。 Schimenti的项目将在项目中绘制影响配子发生的突变，以促进菌落维持，并作为基因克隆的第一步。 Schimenti对项目的重点将是影响减少重组和染色体代谢的突变。 Schimenti将在项目中绘制这些内容，以促进菌落维持，并作为基因克隆的第一步。 Schimenti项目的重点将是影响减数分裂重组和染色体代谢的突变。这些将被映射到高分辨率，并将子集在定位的克隆上。 Handel和Eppig的项目将分别对精子发生或精子功能以及卵子或卵母细胞功能的突变体进行表型分析。此外，将在提供配配分子分析和生殖细胞 - 及性细胞通信的分子分析的项目中开发一组标记基因序列。这些标记基因对于在突变体的配子发生过程中分析基因表达至关重要，提供了分子表型，该表型提供有关停滞阶段以及突变基因作用的下游序列的信息。综上