GENOMICS OF MALE GERM CELL SURVIVAL AND MAINTENANCE MECHANISMS

男性生殖细胞存活和维持机制的基因组学

• 批准号: 7555694
• 负责人: MARY ANN HANDEL
• 金额: $ 21.77万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7555694
• 关键词: Affect; Aneuploidy; Apoptosis; Biological Assay; Cell Communication; Cell Differentiation process; Cell Maturation; Cell Survival; Cells; Chromosome Pairing; Chromosomes; Chromosomes, Human, Pair 1; Competence; Cytology; Development; Doctor of Philosophy; Ensure; Environment; Event; Failure; Fostering; Gene Expression; Genes; Genetic Recombination; Genomics; Germ Cells; Infertility; Interruption; Knowledge; Maintenance; Male Infertility; Maps; Mediating; Meiosis; Meiotic Prophase I; Meiotic Recombination; Modeling; Molecular; Mutation; Pathway interactions; Phenotype; Prophase; Public Health; Regulation; Role; Site; Somatic Cell; Spermatocytes; Staging; Stem cell transplant; Stem cells; Syndrome; Techniques; Testing; Testis; Time; Validation; Work; critical period; design; gene cloning; human male; insight; male; mutant; neuronal cell body; novel; programs; reproductive; sertoli cell; spermatogenic epithelium structure; success; tool

Project II: Genomics of Male Germ Cell Survival and Maintenance Mechanisms Mary Ann Handel, Project Leader Meiosis is particularly vulnerable to interruption and arrest at prophase I stages, which is when two key events are occurring: chromosome recombination/synapsis and passage of germ cells from the basal to the adluminal compartment of the seminiferous epithelium, an environment that fosters completion of meiosis. Although both meiotic recombination events autonomous to the germ cell and seminiferous epithelium events mediated by the Sertoli cells are required for progress beyond this early stage of meiotic prophase, most of the mechanisms remain poorly understood. Mutations generated by the ReproGenomics Program provide opportunities to investigate the testicular regulation of critical events of early meiotic prophase. The spcar1-4, sjsermatocyte arrest 1-4, mutations cause arrest at this early and vulnerable stage of prophase. In Aim 1, the causes and consequences for the germ cell of meiotic arrest will be determined using techniques of molecular cytology and gene expression analysis. Because there is no a priori knowledge whether these mutations act in the germ cell or in the soma to cause spermatocyte arrest, this will be resolved in Aim 2 by spermatogonial stem cell (SSC) transplantation assays. In Aim 3, the downstream effects of the mutations on Sertoli cells will be investigated, using meiotic arrest mutations as a tool to examine aspects of cell-cell interactions and gene expression critical for Sertoli cell maturation and testis differentiation. The genomic regions defined for these mutations do not include any genes known to be involved in meiotic pathways, ensuring that this work will, in the analyses of Aim 4, identify new or unsuspected genes and mechanisms, either intrinsic or extrinsic to the germ cell, essential for meiotic progress. Together the four aims will tackle different aspects of the meiotic arrest phenotypes of different mutations affecting the same stage of meiosis. Relevance to Public Health: By discovery of novel mechanisms controlling early meiotic prophase, this work will provide insight into common human male infertility syndromes and the origins of aneuploidy.

项目二：雄性生殖细胞存活和维持机制的基因组学 玛丽安汉德尔，项目负责人 减数分裂特别容易在前期I阶段中断和停滞，这是两个关键阶段， 染色体重组/联会和生殖细胞从基底细胞到基底细胞的通道 生精上皮的近腔室，促进减数分裂完成的环境。 虽然减数分裂重组事件都是生殖细胞和生精上皮自主的， 由支持细胞介导的事件是超越减数分裂前期的早期阶段所必需的， 对大多数机制仍然知之甚少。ReproGenomics计划产生的突变 提供了机会，研究早期减数分裂前期的关键事件的睾丸调节。的 spcar 1 -4，sjsermatocyte arrest 1-4，突变导致在早期和脆弱的前期阶段的停滞。 在目标1中，将使用以下方法确定生殖细胞减数分裂停滞的原因和后果： 分子细胞学和基因表达分析技术。因为没有先验知识 无论这些突变是在生殖细胞还是在索马中起作用，引起精母细胞停滞， 通过精原干细胞（SSC）移植试验在Aim 2中消退。目标3：下游 将使用减数分裂停滞突变作为工具，研究突变对支持细胞的影响 检查细胞间相互作用和支持细胞成熟和睾丸的关键基因表达方面 分化为这些突变定义的基因组区域不包括任何已知的基因。 参与减数分裂途径，确保这项工作将在目标4的分析中， 未知的基因和机制，无论是内在的或外在的生殖细胞，必要的减数分裂 中求进工作总这四个目标将一起解决不同的减数分裂停滞表型的不同方面， 影响减数分裂同一阶段的突变。 与公共卫生的相关性：通过发现控制早期减数分裂前期的新机制， 这项工作将为人类常见的男性不育症和非整倍体的起源提供深入的了解。